|
1
|
Moein M, Fioramonti P, Lieb K, Golkarieh A, Forouzan A, Leipman J, Bahreini A, Moallem Shahri M, Jamshidi A, Saidi R. Improved Outcomes of Liver Transplantation in Patients With Hepatitis C, Following the Introduction of Innovative Antiviral Therapies. J Clin Exp Hepatol 2025; 15:102428. [PMID: 39564427 PMCID: PMC11570942 DOI: 10.1016/j.jceh.2024.102428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/10/2024] [Indexed: 11/21/2024] Open
Abstract
Background The treatment landscape for hepatitis C virus (HCV) underwent a significant shift with the introduction of direct-acting antiviral (DAA) medications in late 2013. This study aimed to evaluate the impact of DAAs on liver transplantation outcomes, examining both the benefits and any potential drawbacks associated with their use. Methods and materials A retrospective registry analysis of the United Network for Organ Sharing database was done for liver transplants in patients diagnosed with hepatitis C, that were performed in the United States from January 2000 to May 2020. Results The study was divided into two subgroups, based on the timing of the new DAA medication that FDA approved. The only significant difference between the two cohorts is the recipient's age. The data analysis showed a significant overall 5-year graft survival improvement in the 2014-2020 group compared with the 2000-2013 group, from a mean of 64.8% in 2000-2013 to a mean of 76% in 2014-2020 (P < 0.001). Interestingly, when we compared the 5-year graft survivals with recipients who had a donor above age 50, the graft survival rate difference was even more significant (74% vs. 56%, P < 0.001) as some studies have shown a suboptimal graft outcome when the donor age is above 40 years old. Not only has the utilization of donation after circulatory death livers increased significantly after 2014 but the graft survival in this cohort has also been significantly higher (P < 0.001). Conclusion The emergence of DAAs in 2013 marked a watershed moment in the management of HCV offering high cure rates, minimal side effects, and shorter treatment durations to a point that the short- and long-term outcomes of liver transplantation for HCV is almost equal to the other causes of liver transplantation.
Collapse
Affiliation(s)
- Mahmoudreza Moein
- SUNY Upstate Medical University, Division of Transplant Services, Department of Surgery, Syracuse, NY, USA
| | - Peter Fioramonti
- SUNY Upstate Medical University, Division of Transplant Services, Department of Surgery, Syracuse, NY, USA
| | - Kayla Lieb
- SUNY Upstate Medical University, Division of Transplant Services, Department of Surgery, Syracuse, NY, USA
| | - Alireza Golkarieh
- University of Michigan, Department of Mechanical Engineering and Data Science, Ann Arbor, MI, USA
| | - Artin Forouzan
- SUNY Upstate Medical University, Division of Transplant Services, Department of Surgery, Syracuse, NY, USA
| | - Jessica Leipman
- SUNY Upstate Medical University, Division of Transplant Services, Department of Surgery, Syracuse, NY, USA
| | - Amin Bahreini
- SUNY Upstate Medical University, Division of Transplant Services, Department of Surgery, Syracuse, NY, USA
| | - Matin Moallem Shahri
- SUNY Upstate Medical University, Division of Transplant Services, Department of Surgery, Syracuse, NY, USA
| | - Abolfazl Jamshidi
- SUNY Upstate Medical University, Division of Transplant Services, Department of Surgery, Syracuse, NY, USA
| | - Reza Saidi
- SUNY Upstate Medical University, Division of Transplant Services, Department of Surgery, Syracuse, NY, USA
| |
Collapse
|
|
2
|
Peluso P, Dallocchio R, Dessì A, Salgado A, Chankvetadze B, Scriba GKE. Molecular modeling study to unravel complexation of daclatasvir and its enantiomer by β-cyclodextrins. Computational analysis using quantum mechanics and molecular dynamics. Carbohydr Polym 2024; 346:122483. [PMID: 39245475 DOI: 10.1016/j.carbpol.2024.122483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 07/08/2024] [Accepted: 07/09/2024] [Indexed: 09/10/2024]
Abstract
A computational study was performed to unravel mechanisms underlying capillary electrophoresis enantioseparations of daclatasvir and its (R,R,R,R)-enantiomer with native and methylated β-cyclodextrins (β-CDs) as chiral selectors. Considering the enantioseparation results as benchmark, the structures of β-CD and seven methylated β-CDs were optimized by quantum mechanics, and their topography and computed molecular properties were compared. Furthermore, the electron charge density distribution of the macrocycles was also evaluated by calculating the molecular electrostatic potential of pivotal regions of native and methylated β-CDs. The function of hydrogen bonds in the complexation process of daclatasvir and the CDs was derived from quantum mechanics analysis and confirmed by molecular dynamics, as orthogonal computational techniques. The presence of a round-shaped cavity in the CDs used as chiral selector appeared as a necessary requirement for the enantioseparation of daclatasvir and its (R,R,R,R)-enantiomer. In this regard, it was confirmed that the round shape of the CDs is sustained by hydrogen bonds formed between adjacent glucopyranose units and blocking rotation of the linking glycosidic bonds. The presence of hydroxy groups at the 6-position of the glucopyranose units and the concurrent absence of hydroxy groups at the 2-position were evidenced as important factors for enantioseparation of daclatasvir and its enantiomer by methylated β-CDs.
Collapse
Affiliation(s)
- Paola Peluso
- Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Traversa La Crucca, 3 - Regione Baldinca - Li Punti, 07100 Sassari, Italy.
| | - Roberto Dallocchio
- Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Traversa La Crucca, 3 - Regione Baldinca - Li Punti, 07100 Sassari, Italy
| | - Alessandro Dessì
- Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Traversa La Crucca, 3 - Regione Baldinca - Li Punti, 07100 Sassari, Italy
| | - Antonio Salgado
- University of Alcalá, NMR Spectroscopy Centre (CERMN), CAI Químicas, Faculty of Pharmacy, 28805 Alcalá de Henares, Madrid, Spain
| | - Bezhan Chankvetadze
- Institute of Physical and Analytical Chemistry, School of Exact and Natural Sciences, Tbilisi State University, 0179 Tbilisi, Georgia
| | - Gerhard K E Scriba
- Friedrich Schiller University Jena, Department of Pharmaceutical/Medicinal Chemistry, Philosophenweg 14, 07743 Jena, Germany.
| |
Collapse
|
|
3
|
Sun M, Lv S, Pan Y, Song Q, Ma C, Yu M, Gao X, Guo X, Wang S, Gao Z, Wang S, Meng Q, Zhang L, Li Y. Discovery of Daclatasvir as a potential PD-L1 inhibitor from drug repurposing. Bioorg Chem 2024; 153:107874. [PMID: 39418845 DOI: 10.1016/j.bioorg.2024.107874] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 10/03/2024] [Accepted: 10/04/2024] [Indexed: 10/19/2024]
Abstract
This study employed a drug repositioning strategy to discover novel PD-L1 small molecule inhibitors. 3D-QSAR pharmacophore models were establishedand subsequently validated through various means to select a robust model, Hypo-1, suitable for virtual screening. Hypo1 was used toscreen a library of 7,475 compounds from the Drugbank database, leading to the identification of 283 molecules following molecular docking with PD-L1.19 compounds underwent HTRF assays, with 15 showing varying degrees of inhibition of the PD-1/PD-L1 interaction. Compounds2202,2204,2207, and2208were further confirmed to bind to PD-L1 using SPR experiments. Among them, compound2204(Daclatasvir, KD = 11.4 μM) showeda higher affinity for human PD-L1 than the control compound BMS-1. In the HepG2/Jurkat cell co-culture model, Daclatasvir effectively activated Jurkat cells to kill HepG2 cells. In the mouse H22 hepatocellular tumor model, Daclatasvir significantly inhibited tumor growth (TGI = 53.4 % at a dose of 100 mg/kg). Its anti-tumor effect was more pronounced when combined with Lenvatinib (TGI = 85.1 %). Flow cytometry analysis of splenocytes and tumor cells indicated that Daclatasvir activated the immune system in both models. In summary, Daclatasvir was identified as a novel PD-L1small molecule inhibitor.
Collapse
Affiliation(s)
- Mengmeng Sun
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024
| | - Shixuan Lv
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024
| | - Yanyan Pan
- Department of Central Laboratory, Dalian Municipal Central Hospital, Dalian, Liaoning, China, 116023
| | - Qiling Song
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024
| | - Chunyan Ma
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024
| | - Menglin Yu
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024
| | - Xinru Gao
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024
| | - Xiuhan Guo
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024; Ningbo Institute of Dalian University of Technology, No.26 Yucai Road, Jiangbei District, Ningbo, China, 315016
| | - Shisheng Wang
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024; Ningbo Institute of Dalian University of Technology, No.26 Yucai Road, Jiangbei District, Ningbo, China, 315016
| | - Zhigang Gao
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024; Ningbo Institute of Dalian University of Technology, No.26 Yucai Road, Jiangbei District, Ningbo, China, 315016
| | - Shuai Wang
- Ningbo Institute of Dalian University of Technology, No.26 Yucai Road, Jiangbei District, Ningbo, China, 315016
| | - Qingwei Meng
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024; Ningbo Institute of Dalian University of Technology, No.26 Yucai Road, Jiangbei District, Ningbo, China, 315016
| | - Li Zhang
- Department of Central Laboratory, Dalian Municipal Central Hospital, Dalian, Liaoning, China, 116023
| | - Yueqing Li
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning, China, 116024; Ningbo Institute of Dalian University of Technology, No.26 Yucai Road, Jiangbei District, Ningbo, China, 315016.
| |
Collapse
|
|
4
|
Kubyshkin V, Mykhailiuk PK. Proline Analogues in Drug Design: Current Trends and Future Prospects. J Med Chem 2024; 67:20022-20055. [PMID: 39605166 DOI: 10.1021/acs.jmedchem.4c01987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Proline analogues are versatile chemical building blocks that enable modular construction of small-molecule drugs and pharmaceutical peptides. Over the past 15 years, the FDA has approved over 15 drugs containing proline analogues in their structures, five in the last three years alone (daridorexant, trofinetide, nirmatrelvir, rezafungin, danicopan). This perspective offers an analysis of the most common types of proline analogues currently trending in drug design. We focus on examples of fluoroprolines, α-methylproline, bicyclic proline analogues, and aminoprolines, while also highlighting proline analogues that remain underrepresented. We supplement our analysis with physicochemical information regarding the specific molecular properties of these moieties. Additionally, we discuss several intriguing cases where nonproline residues were replaced with proline analogues as a strategy to eliminate unwanted hydrogen bond donor sites. In conclusion, we present some suggestions for the future exploration of this promising class of molecular entities in drug discovery.
Collapse
|
|
5
|
Pennington LD, Hesse MJ, Koester DC, McAtee RC, Qunies AM, Hu DX. Property-Based Drug Design Merits a Nobel Prize. J Med Chem 2024; 67:11452-11458. [PMID: 38940466 DOI: 10.1021/acs.jmedchem.4c01345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2024]
Affiliation(s)
| | | | | | - Rory C McAtee
- Drug Hunter, Happy Valley, Oregon 97086, United States
| | | | - Dennis X Hu
- Drug Hunter, Happy Valley, Oregon 97086, United States
| |
Collapse
|
|
6
|
Rej RK, Allu SR, Roy J, Acharyya RK, Kiran INC, Addepalli Y, Dhamodharan V. Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs. Pharmaceuticals (Basel) 2024; 17:494. [PMID: 38675453 PMCID: PMC11054475 DOI: 10.3390/ph17040494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/02/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality that show promise to open a target space not accessible to conventional small molecules via a degradation-based mechanism. PROTAC degraders, due to their bifunctional nature, which is categorized as 'beyond the Rule of Five', have gained attention as a distinctive therapeutic approach for oral administration in clinical settings. However, the development of PROTACs with adequate oral bioavailability remains a significant hurdle, largely due to their large size and less than ideal physical and chemical properties. This review encapsulates the latest advancements in orally delivered PROTACs that have entered clinical evaluation as well as developments highlighted in recent scholarly articles. The insights and methodologies elaborated upon in this review could be instrumental in supporting the discovery and refinement of novel PROTAC degraders aimed at the treatment of various human cancers.
Collapse
Affiliation(s)
- Rohan Kalyan Rej
- Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.A.); (R.K.A.)
| | - Srinivasa Rao Allu
- Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.A.); (R.K.A.)
| | - Joyeeta Roy
- Rogel Cancer Center, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Ranjan Kumar Acharyya
- Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (S.R.A.); (R.K.A.)
| | - I. N. Chaithanya Kiran
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02139, USA;
| | - Yesu Addepalli
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
| | - V. Dhamodharan
- Institute of Organic Chemistry, Center for Nanosystems Chemistry, University of Wuerzburg, Am Hubland, 97074 Würzburg, Germany;
| |
Collapse
|
|
7
|
Möbitz H. Design Principles for Balancing Lipophilicity and Permeability in beyond Rule of 5 Space. ChemMedChem 2024; 19:e202300395. [PMID: 37986275 DOI: 10.1002/cmdc.202300395] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/13/2023] [Accepted: 11/16/2023] [Indexed: 11/22/2023]
Abstract
An ab initio conformational analysis of oral beyond Rule of 5 (bRo5) drugs was complemented with measured permeability and logP(octanol) to derive design principles conferring oral bioavailability. 3D polar surface area (PSA) thresholds for oral bRo5 drugs coincided with those reported for Ro5 space. The majority of oral bRo5 drugs exceeded the Ro5 logP threshold of 5, reflecting a bias for permeability. Above 500 Da molecular weight (MW), oral drugs and highly permeable Novartis compounds occupy a narrow polarity range (topological or TPSA/MW) of 0.1-0.3 Å2 /Da, whose upper half coincides with the lower 90 percentiles of the Novartis logP set. This TPSA/MW range and 3D PSA below 100 Å2 define the "Rule of ~1 /₅" for balancing lipophilicity and permeability. Neutral TPSA, defined as TPSA minus 3D PSA occurs independent of conformation, intramolecular hydrogen bonds (IMHB) and MW, suggesting it is an intrinsic molecular property. Neutral TPSA increased in the lead optimization (LO) campaigns of three first in class de novo designed bRo5 drugs and may be a useful design parameter in bRo5 space.
Collapse
Affiliation(s)
- Henrik Möbitz
- Computer-Aided Drug Design, Global Discovery Chemistry, Novartis BioMedical Research, 4002, Basel, Switzerland
| |
Collapse
|
|
8
|
Teng M, Gray NS. The rise of degrader drugs. Cell Chem Biol 2023; 30:864-878. [PMID: 37494935 DOI: 10.1016/j.chembiol.2023.06.020] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/30/2023] [Accepted: 06/21/2023] [Indexed: 07/28/2023]
Abstract
The cancer genomics revolution has served up a plethora of promising and challenging targets for the drug discovery community. The field of targeted protein degradation (TPD) uses small molecules to reprogram the protein homeostasis system to destroy desired target proteins. In the last decade, remarkable progress has enabled the rational development of degraders for a large number of target proteins, with over 20 molecules targeting more than 12 proteins entering clinical development. While TPD has been fully credentialed by the prior development of immunomodulatory drug (IMiD) class for the treatment of multiple myeloma, the field is poised for a "Gleevec moment" in which robust clinical efficacy of a rationally developed novel degrader against a preselected target is firmly established. Here, we endeavor to provide a high-level evaluation of exciting developments in the field and comment on steps that may realize the full potential of this new therapeutic modality.
Collapse
Affiliation(s)
- Mingxing Teng
- Center for Drug Discovery, Department of Pathology & Immunology, and Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Nathanael S Gray
- Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA 94305, USA.
| |
Collapse
|
|
9
|
Rotella DP. Successes in antiviral drug discovery: a tribute to Nick Meanwell. Med Chem Res 2023; 32:1-10. [PMID: 37362321 PMCID: PMC10249547 DOI: 10.1007/s00044-023-03086-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/15/2023] [Indexed: 06/28/2023]
Abstract
Drug discovery is a difficult task, and is even more challenging when the target evolves during therapy. Antiviral drug therapy is an excellent example, exemplified by the evolution of therapeutic approaches for treatment of hepatitis C and HIV-1. Nick Meanwell and his colleagues made important contributions leading to molecules for treatment of hepatitis C and HIV-1, each with distinct mechanisms of action. This review summarizes the discovery and impact of these drugs, and will highlight, where applicable, the broader contributions of these discoveries to medicinal chemistry and drug discovery.
Collapse
Affiliation(s)
- David P. Rotella
- Department of Chemistry and Biochemistry, Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, NJ 07043 USA
| |
Collapse
|
|
10
|
Wieske LHE, Atilaw Y, Poongavanam V, Erdélyi M, Kihlberg J. Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds. Chemistry 2023; 29:e202202798. [PMID: 36286339 PMCID: PMC10107787 DOI: 10.1002/chem.202202798] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/23/2022] [Accepted: 10/25/2022] [Indexed: 12/15/2022]
Abstract
The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d6 ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.
Collapse
Affiliation(s)
- Lianne H E Wieske
- Department of Chemistry - BMC, Uppsala University, Box 576, SE-751 23, Uppsala, Sweden
| | - Yoseph Atilaw
- Department of Chemistry - BMC, Uppsala University, Box 576, SE-751 23, Uppsala, Sweden
| | | | - Máté Erdélyi
- Department of Chemistry - BMC, Uppsala University, Box 576, SE-751 23, Uppsala, Sweden
| | - Jan Kihlberg
- Department of Chemistry - BMC, Uppsala University, Box 576, SE-751 23, Uppsala, Sweden
| |
Collapse
|
|
11
|
Flick AC, Leverett CA, Ding HX, McInturff EL, Fink SJ, Mahapatra S, Carney DW, Lindsey EA, DeForest JC, France SP, Berritt S, Bigi-Botterill SV, Gibson TS, Watson RB, Liu Y, O'Donnell CJ. Synthetic Approaches to the New Drugs Approved During 2020. J Med Chem 2022; 65:9607-9661. [PMID: 35833579 DOI: 10.1021/acs.jmedchem.2c00710] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.
Collapse
Affiliation(s)
- Andrew C Flick
- Takeda Pharmaceuticals, 9625 Towne Centre Drive, San Diego, California 92121, United States
| | - Carolyn A Leverett
- Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, Connecticut 06340, United States
| | - Hong X Ding
- Pharmacodia (Beijing) Co. Ltd., Beijing 100085, China
| | - Emma L McInturff
- Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, Connecticut 06340, United States
| | - Sarah J Fink
- Takeda Pharmaceuticals, 125 Binney Street, Cambridge, Massachusetts 02142, United States
| | - Subham Mahapatra
- Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, Connecticut 06340, United States
| | - Daniel W Carney
- Takeda Pharmaceuticals, 9625 Towne Centre Drive, San Diego, California 92121, United States
| | - Erick A Lindsey
- Takeda Pharmaceuticals, 9625 Towne Centre Drive, San Diego, California 92121, United States
| | - Jacob C DeForest
- Pfizer Worldwide Research and Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, California 92121, United States
| | - Scott P France
- Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, Connecticut 06340, United States
| | - Simon Berritt
- Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, Connecticut 06340, United States
| | | | - Tony S Gibson
- Takeda Pharmaceuticals, 9625 Towne Centre Drive, San Diego, California 92121, United States
| | - Rebecca B Watson
- Pfizer Worldwide Research and Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, California 92121, United States
| | - Yiyang Liu
- Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, Connecticut 06340, United States
| | - Christopher J O'Donnell
- Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, Connecticut 06340, United States
| |
Collapse
|
|
12
|
Complexation of daclatasvir by single isomer methylated β-cyclodextrins studied by capillary electrophoresis, NMR spectroscopy and mass spectrometry. Carbohydr Polym 2021; 273:118486. [PMID: 34560933 DOI: 10.1016/j.carbpol.2021.118486] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/06/2021] [Accepted: 07/22/2021] [Indexed: 11/23/2022]
Abstract
In capillary electrophoresis an enantioseparation of daclatasvir (DCV) was observed in case of heptakis(2,6-di-O-methyl)-β-CD, heptakis(2-O-methyl)-β-CD and β-CD, while two peaks with a plateau were noted for heptakis(2,3,6-tri-O-methyl)-β-CD and heptakis(2,3-di-O-methyl)-β-CD indicating a slow equilibrium. Heptakis(6-O-methyl)-β-CD and heptakis(3-O-methyl)-β-CD yielded broad peaks. Nuclear magnetic resonance experiments including nuclear Overhauser effect-based techniques revealed inclusion complex formation for all CDs with the biphenyl ring of DCV within the cavity and the valine-pyrrolidine moieties protruding from the torus. However, in case of heptakis(2,6-di-O-methyl)-β-CD, heptakis(2-O-methyl)-β-CD and β-CD higher order structures with 1:3 stoichiometry were concluded, where the valine moieties enter additional CD molecules via the secondary side. Heptakis(2,3,6-tri-O-methyl)-β-CD and heptakis(2,3-di-O-methyl)-β-CD yielded primarily 1:1 complexes. Higher order complexes between DCV and heptakis(2,6-di-O-methyl)-β-CD were corroborated by mass spectrometry. Complex stoichiometry was not the reason for the slow equilibrium yielding the plateau observed in capillary electrophoresis, but structural characteristics of the CDs especially complete methylation of the secondary rim.
Collapse
|
|
13
|
Kazmierski WM, Miriyala N, Johnson DK, Baskaran S. The Discovery of Conformationally Constrained Bicyclic Peptidomimetics as Potent Hepatitis C NS5A Inhibitors. ACS Med Chem Lett 2021; 12:1649-1655. [PMID: 34790290 PMCID: PMC8591741 DOI: 10.1021/acsmedchemlett.1c00391] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Indexed: 01/03/2023] Open
Abstract
![]()
HCV NS5A inhibitors are the backbone
of directly acting antiviral
treatments against the hepatitis C virus (HCV). While these therapies
are generally highly curative, they are less effective in some specific
HCV patient populations. In the search for broader-acting HCV NS5A
inhibitors that address these needs, we explored conformational restrictions
imposed by the [7,5]-azabicyclic lactam moiety incorporated into daclatasvir
(1) and related HCV NS5A inhibitors. Unexpectedly, compound 5 was identified as a potent HCV genotype 1a and 1b inhibitor.
Molecular modeling of 5 bound to HCV genotype 1a suggested
that the use of the conformationally restricted lactam moiety might
have resulted in reorientation of its N-terminal carbamate to expose
a new interaction with the NS5A pocket located between amino acids
P97 and Y93, which was not easily accessible to 1. The
results also suggest new chemistry directions that exploit the interactions
with the P97–Y93 site toward new and potentially improved HCV
NS5A inhibitors.
Collapse
Affiliation(s)
- Wieslaw M. Kazmierski
- GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States
| | - Nagaraju Miriyala
- GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States
| | - David K. Johnson
- Computational Chemical Biology Core and Molecular Graphics and Modeling Laboratory, University of Kansas, Lawrence, Kansas 66047, United States
| | - Sam Baskaran
- GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States
| |
Collapse
|
|
14
|
Krait S, Salgado A, Malanga M, Sohajda T, Benkovics G, Szakály PS, Chankvetadze B, Scriba GKE. Structural characterization of methyl-β-cyclodextrins by high-performance liquid chromatography and nuclear magnetic resonance spectroscopy and effect of their isomeric composition on the capillary electrophoresis enantioseparation of daclatasvir. J Chromatogr A 2021; 1661:462675. [PMID: 34890854 DOI: 10.1016/j.chroma.2021.462675] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/20/2021] [Accepted: 11/04/2021] [Indexed: 10/19/2022]
Abstract
The separation of daclatasvir and its R,R,R,R-enantiomer was studied by capillary electrophoresis using various randomly methylated β-CDs and the single isomer heptakis(2,6-di-O-methyl)-β-CD (2,6-DM-β-CD) as chiral selectors in an acidic background electrolyte. Opposite enantiomer migration order was observed for randomly substituted CDs compared to 2,6-DM-β-CD as well as methylated β-CDs with different composition according to the specifications of the manufacturers. HPLC and NMR analyses confirmed that the presence of a high 2,6-DM-β-CD content in the CDs enables to achieve the migration order R,R,R,R-enantiomer > daclatasvir. In contrast, products with low 2,6-DM-β-CD isomer content and/or the presence of a large amount of methylated CD isomers, in which d-glucopyranose moieties are not substituted in either position 2 or 6, displayed the opposite enantiomer migration order daclatasvir > R,R,R,R-enantiomer. The study indicated the importance of the type and composition of derivatized CDs on chiral separations in capillary electrophoresis as well as the importance of proper quality control for cyclodextrin manufacturers. Moreover, the observed migration order could be rationalized based on the composition and substitution pattern of the CDs.
Collapse
Affiliation(s)
- Sulaiman Krait
- Department of Pharmaceutical/Medicinal Chemistry, Friedrich-Schiller-University Jena, Philosophenweg 14, Jena 07743, Germany
| | - Antonio Salgado
- NMR Spectroscopy Center (CERMN), CAI Químicas, Faculty of Pharmacy, University of Alcalá, Madrid, Alcalá de Henares 28805, Spain
| | - Milo Malanga
- CycloLab Ltd., Illatos út 7, Budapest 1097, Hungary
| | | | | | | | - Bezhan Chankvetadze
- Institute of Physical and Analytical Chemistry, School of Exact and Natural Sciences, Tbilisi State University, Tbilisi 0179, Georgia
| | - Gerhard K E Scriba
- Department of Pharmaceutical/Medicinal Chemistry, Friedrich-Schiller-University Jena, Philosophenweg 14, Jena 07743, Germany.
| |
Collapse
|
|
15
|
Xie H, Liu H, Zhang Y, Huang E, Feng Y, Xiang X, Fang Q, Peng Z, Dong W, An D. Development of a Synthesis Process for a Novel HCV NS5A Inhibitor, Emitasvir. Org Process Res Dev 2021. [DOI: 10.1021/acs.oprd.0c00519] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Hongming Xie
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Haiwang Liu
- The State Key Laboratory of Anti-Infective Drug Development (No. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Yingjun Zhang
- The State Key Laboratory of Anti-Infective Drug Development (No. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Enhuo Huang
- The State Key Laboratory of Anti-Infective Drug Development (No. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Yahui Feng
- HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China
| | - Xuwen Xiang
- HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China
| | - Qinghong Fang
- The State Key Laboratory of Anti-Infective Drug Development (No. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Zhihong Peng
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Wanrong Dong
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Delie An
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| |
Collapse
|
|
16
|
Carbamate group as structural motif in drugs: a review of carbamate derivatives used as therapeutic agents. Arh Hig Rada Toksikol 2020; 71:285-299. [PMID: 33410773 PMCID: PMC7968508 DOI: 10.2478/aiht-2020-71-3466] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 12/01/2020] [Indexed: 12/17/2022] Open
Abstract
Due to their very good chemical and proteolytic stability, ability to penetrate cell membranes, and resemblance to a peptide bond, carbamate derivatives have received much attention in recent years and got an important role in modern drug discovery and medicinal chemistry. Today, carbamates make structural and/or functional part of many drugs and prodrugs approved and marketed for the treatment of various diseases such as cancer, epilepsy, hepatitis C, HIV infection, and Alzheimer's disease. In drugs they can play a role in drug-target interaction or improve the biological activity of parent molecules. In prodrugs they are mainly used to delay first-pass metabolism and enhance the bioavailability and effectiveness of compounds. This brief review takes a look at the properties and use of carbamates in various fields of medicine and provides quick insights into the mechanisms of action for some of them.
Collapse
|
|
17
|
Affiliation(s)
- Nicholas A Meanwell
- Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, United States
| | - Gunda I Georg
- College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States
| | - Shaomeng Wang
- University of Michigan, Departments of Internal Medicine, Pharmacology and Medicinal Chemistry and Michigan Center for Therapeutic Innovation, Ann Arbor, Michigan 48109, United States
| |
Collapse
|
|
18
|
Sumoto K. [Synthetic Studies on Developments for Bioactive New Leads of Oligovalent Symmetrical Molecules]. YAKUGAKU ZASSHI 2020; 140:529-541. [PMID: 32238636 DOI: 10.1248/yakushi.19-00222] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Interactions between carbohydrate-containing glycoproteins, proteoglycans, and glycolipids on the cell surface are important biological stages for the processes of bacterial or viral infection and tumor metastasis. Moreover, supramolecular interaction by macromolecules with two-fold (C2) or three-fold (C3) geometry is one of the common interactions in many important biological responses. To develop new multivalent symmetrical bioactive compounds or leads, we designed and synthesized several new molecules with these geometries and evaluated their bioactivities in an attempt to find new types of bioactive leads that may interfere with the sugar recognition process. We evaluated bioactivities including antibacterial, antiviral, and anticancer activities of targeted molecules in vitro using biological assay systems. Among the synthesized target derivatives examined, some bivalent symmetrical derivatives showed high levels of bioactivities. In this review, the author describes the results of synthesis of oligovalent symmetrical target compounds and some interesting guiding results of evaluation of their biological activities and structure-activity relationships.
Collapse
|
|
19
|
Krait S, Salgado A, Villani C, Naumann L, Neusüß C, Chankvetadze B, Scriba GK. Unusual complexation behavior between daclatasvir and γ-Cyclodextrin. A multiplatform study. J Chromatogr A 2020; 1628:461448. [DOI: 10.1016/j.chroma.2020.461448] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/30/2020] [Accepted: 08/01/2020] [Indexed: 12/14/2022]
|
|
20
|
Liu J, Han J, Izawa K, Sato T, White S, Meanwell NA, Soloshonok VA. Cyclic tailor-made amino acids in the design of modern pharmaceuticals. Eur J Med Chem 2020; 208:112736. [PMID: 32966895 DOI: 10.1016/j.ejmech.2020.112736] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 12/15/2022]
Abstract
Tailor-made AAs are indispensable components of modern medicinal chemistry and are becoming increasingly prominent in new drugs. In fact, about 30% of small-molecule pharmaceuticals contain residues of tailor-made AAs or structurally related diamines and amino-alcohols. Cyclic tailor-made AAs present a particular value to rational structural design by virtue of their local conformational constraints and are widely used in lead optimization programs. The present review article highlights 34 compounds, all of which are derived from cyclic AAs, representing recently-approved, small-molecule pharmaceuticals as well as promising drug candidates currently in various phases of clinical study. For each compound, the discussion includes the discovery, therapeutic profile and optimized synthesis, with a focus on the preparation of cyclic tailor-made AA as the principal structural feature. The present review article is intended to serve as a reference source for organic, medicinal and process chemists along with other professionals working in the fields of drug design and pharmaceutical discovery.
Collapse
Affiliation(s)
- Jiang Liu
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, Jiangsu, China
| | - Jianlin Han
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, Jiangsu, China
| | - Kunisuke Izawa
- Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, 533-0024, Japan.
| | - Tatsunori Sato
- Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, 533-0024, Japan
| | - Sarah White
- Oakwood Chemical, Inc, 730 Columbia Hwy. N, Estill, SC, 29918, USA
| | - Nicholas A Meanwell
- Department of Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, PO Box, 4000, Princeton, NJ, 08543 4000, United States
| | - Vadim A Soloshonok
- Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018, San Sebastián, Spain; IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013, Bilbao, Spain.
| |
Collapse
|
|
21
|
Nakamura H, Akagi Y, Terui T, Fujioka S, Komoda Y, Kinoshita W, Maeda K, Ukaji Y, Inaba T. Discovery of a novel unsymmetrical structural class of HCV NS5A inhibitors with low picomolar antiviral activity. Bioorg Med Chem Lett 2019; 30:126932. [PMID: 31952964 DOI: 10.1016/j.bmcl.2019.126932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 12/20/2019] [Accepted: 12/23/2019] [Indexed: 11/25/2022]
Abstract
A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC50 values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC50 in the low nanomolar range.
Collapse
Affiliation(s)
- Hiroshi Nakamura
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan; Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
| | - Yusuke Akagi
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Takashi Terui
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Shingo Fujioka
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Yasumasa Komoda
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Wataru Kinoshita
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Kimiya Maeda
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Yutaka Ukaji
- Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan
| | - Takashi Inaba
- Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| |
Collapse
|
|
22
|
Ramdas V, Talwar R, Banerjee M, Joshi AA, Das AK, Walke DS, Borhade P, Dhayagude U, Loriya R, Gote G, Bommakanti A, Sivaram A, Agarwal G, Goswami A, Nigade P, Mehta M, Patil V, Modi D, Kumar H, Mallurwar S, Dash A, Modi F, Kuldharan S, Srivastava P, Singh M, Narasimham L, Gundu J, Sharma S, Kamboj RK, Palle VP. Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate. J Med Chem 2019; 62:10563-10582. [PMID: 31710479 DOI: 10.1021/acs.jmedchem.9b01562] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.
Collapse
Affiliation(s)
- Vidya Ramdas
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Rashmi Talwar
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Moloy Banerjee
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Advait Arun Joshi
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Amit Kumar Das
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Deepak Sahebrao Walke
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Prashant Borhade
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Usha Dhayagude
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Rajesh Loriya
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Ganesh Gote
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Apparao Bommakanti
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Aruna Sivaram
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Gautam Agarwal
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Arnab Goswami
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Prashant Nigade
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Maneesh Mehta
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Vinod Patil
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Dipak Modi
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Hemant Kumar
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Sadanand Mallurwar
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Amruta Dash
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Falguni Modi
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Sandip Kuldharan
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Pratima Srivastava
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Minakshi Singh
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Lakshmi Narasimham
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Jayasagar Gundu
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Sharad Sharma
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Rajender Kumar Kamboj
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| | - Venkata P Palle
- Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India
| |
Collapse
|
|
23
|
Tyagi M, Begnini F, Poongavanam V, Doak BC, Kihlberg J. Drug Syntheses Beyond the Rule of 5. Chemistry 2019; 26:49-88. [DOI: 10.1002/chem.201902716] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/20/2019] [Indexed: 01/26/2023]
Affiliation(s)
- Mohit Tyagi
- Department of Chemistry–BMC Uppsala University Box 576 75123 Uppsala Sweden
| | - Fabio Begnini
- Department of Chemistry–BMC Uppsala University Box 576 75123 Uppsala Sweden
| | | | - Bradley C. Doak
- Department of Medicinal Chemistry, MIPS Monash University 381 Royal Parade Parkville Victoria 3052 Australia
| | - Jan Kihlberg
- Department of Chemistry–BMC Uppsala University Box 576 75123 Uppsala Sweden
| |
Collapse
|
|
24
|
Sofia MJ. The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex. ACTA ACUST UNITED AC 2019. [PMCID: PMC7122418 DOI: 10.1007/7355_2018_47] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
25
|
Sun S, Jia Q, Zhang Z. Applications of amide isosteres in medicinal chemistry. Bioorg Med Chem Lett 2019; 29:2535-2550. [PMID: 31377035 DOI: 10.1016/j.bmcl.2019.07.033] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 07/17/2019] [Accepted: 07/19/2019] [Indexed: 12/18/2022]
Abstract
Isosteric replacement of amide groups is a classic practice in medicinal chemistry. This digest highlights the applications of most commonly employed amide isosteres in drug design aiming at improving potency and selectivity, optimizing physicochemical and pharmacokinetic properties, eliminating or modifying toxicophores, as well as providing novel intellectual property of lead compounds.
Collapse
Affiliation(s)
- Shaoyi Sun
- Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
| | - Qi Jia
- Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada
| | - Zaihui Zhang
- Signalchem Lifesciences Corp., 110-13210, Vanier Place, Richmond, BC V6V 2J2, Canada
| |
Collapse
|
|
26
|
Feng Y, Wang Z, Luo Z, Lai J, Xie H, Luo Z, Zhang L, Li R, Zhang Y. Development of an Efficient and Scalable Biocatalytic Route to (1 S,4 R)-8-Hydroxy-1,2,3,4- tetrahydro-1,4-methanonaphthalen-5-yl Propionate via Enantioselective Enzymatic Desymmetrization of a Prochiral Diester. Org Process Res Dev 2019; 23:1243-1251. [DOI: 10.1021/acs.oprd.9b00188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Yahui Feng
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510640, P. R. China
| | - Zhongqing Wang
- HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China
| | - Zhonghua Luo
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510640, P. R. China
| | - Jinqiang Lai
- HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China
| | - Hongming Xie
- HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China
- Anti-infection Innovation Department, New Drug Research Institute, HEC Pharm Group, Dongguan 523871, P. R. China
| | - Zhenxiu Luo
- HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China
| | - Lei Zhang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510640, P. R. China
| | - Ridong Li
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University, Beijing 100191, P. R. China
| | - Yingjun Zhang
- HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China
- Anti-infection Innovation Department, New Drug Research Institute, HEC Pharm Group, Dongguan 523871, P. R. China
| |
Collapse
|
|
27
|
Sofia MJ. The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032). TOPICS IN MEDICINAL CHEMISTRY 2019. [PMCID: PMC7123690 DOI: 10.1007/7355_2018_58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The discovery of asunaprevir (1) began with the concept of engaging the small and well-defined S1’ pocket of the hepatitis C virus (HCV) NS3/4A protease that was explored in the context of tripeptide carboxylic acid-based inhibitors. A cyclopropyl-acyl sulfonamide moiety was found to be the optimal element at the P1-P1’ interface enhancing the potency of carboxylic acid-based prototypes by 10- to >100-fold, dependent upon the specific background. Optimization for oral bioavailability identified a 1-substituted isoquinoline-based P2* element that conferred a significant exposure advantage in rats compared to the matched 4-substituted quinoline isomer. BMS-605339 (30) was the first cyclopropyl-acyl sulfonamide derivative advanced into clinical trials that demonstrated dose-related reductions in plasma viral RNA in HCV-infected patients. However, 30 was associated with cardiac events observed in a normal healthy volunteer (NHV) and an HCV-infected patient that led to the suspension of the development program. Using a Langendorff rabbit heart model, a limited structure-cardiac liability relationship was quickly established that led to the discovery of 1. This compound, which differs from 30 only by changes in the substitution pattern of the P2* isoquinoline heterocycle and the addition of a single chlorine atom to the molecular formula, gave a dose-dependent reduction in plasma viral RNA following oral administration to HCV-infected patients without the burden of the cardiac events that had been observed with 30. A small clinical trial of the combination of 1 with the HCV NS5A inhibitor daclatasvir (2) established for the first time that a chronic genotype 1 (GT-1) HCV infection could be cured by therapy with two direct-acting antiviral agents in the absence of exogenous immune-stimulating agents. Development of the combination of 1 and 2 was initially focused on Japan where the patient population is predominantly infected with GT-1b virus, culminating in marketing approval which was granted on July 4, 2014. In order to broaden therapy to include GT-1a infections, a fixed dose triple combination of 1, 2, and the allosteric NS5B inhibitor beclabuvir (3) was developed, approved by the Japanese health authorities for the treatment of HCV GT-1 infection on December 20, 2016 and marketed as Ximency®.
Collapse
|
|
28
|
Ashraf MU, Iman K, Khalid MF, Salman HM, Shafi T, Rafi M, Javaid N, Hussain R, Ahmad F, Shahzad-Ul-Hussan S, Mirza S, Shafiq M, Afzal S, Hamera S, Anwar S, Qazi R, Idrees M, Qureshi SA, Chaudhary SU. Evolution of efficacious pangenotypic hepatitis C virus therapies. Med Res Rev 2018; 39:1091-1136. [PMID: 30506705 DOI: 10.1002/med.21554] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 10/11/2018] [Accepted: 10/11/2018] [Indexed: 12/12/2022]
Abstract
Hepatitis C compromises the quality of life of more than 350 million individuals worldwide. Over the last decade, therapeutic regimens for treating hepatitis C virus (HCV) infections have undergone rapid advancements. Initially, structure-based drug design was used to develop molecules that inhibit viral enzymes. Subsequently, establishment of cell-based replicon systems enabled investigations into various stages of HCV life cycle including its entry, replication, translation, and assembly, as well as role of host proteins. Collectively, these approaches have facilitated identification of important molecules that are deemed essential for HCV life cycle. The expanded set of putative virus and host-encoded targets has brought us one step closer to developing robust strategies for efficacious, pangenotypic, and well-tolerated medicines against HCV. Herein, we provide an overview of the development of various classes of virus and host-directed therapies that are currently in use along with others that are undergoing clinical evaluation.
Collapse
Affiliation(s)
- Muhammad Usman Ashraf
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.,Virology Laboratory, Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Kanzal Iman
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Muhammad Farhan Khalid
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.,Department of Biomedical Engineering, University of Engineering and Technology, Lahore, Pakistan
| | - Hafiz Muhammad Salman
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.,Plant Biotechnology Laboratory, Institute of Agricultural Sciences, University of the Punjab, Lahore, Pakistan
| | - Talha Shafi
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Momal Rafi
- Department of Statistics, University of Gujrat, Gujrat, Pakistan
| | - Nida Javaid
- Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Rashid Hussain
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Fayyaz Ahmad
- Department of Statistics, University of Gujrat, Gujrat, Pakistan
| | | | - Shaper Mirza
- Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Muhammad Shafiq
- Plant Biotechnology Laboratory, Institute of Agricultural Sciences, University of the Punjab, Lahore, Pakistan
| | - Samia Afzal
- Virology Laboratory, Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Sadia Hamera
- Department of Plant Genetics, Institute of Life Sciences, University of Rostock, Germany
| | - Saima Anwar
- Department of Biomedical Engineering, University of Engineering and Technology, Lahore, Pakistan
| | - Romena Qazi
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan
| | - Muhammad Idrees
- Virology Laboratory, Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.,Hazara University, Mansehra, Pakistan
| | - Sohail A Qureshi
- Institute of Integrative Biosciences, CECOS-University of Information Technology and Emerging Sciences, Peshawar, Pakistan
| | - Safee Ullah Chaudhary
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| |
Collapse
|
|
29
|
Gadhachanda VR, Eastman KJ, Wang Q, Phadke AS, Patel D, Yang W, Marlor CW, Deshpande M, Huang M, Wiles JA. Ferrocene-based inhibitors of hepatitis C virus replication that target NS5A with low picomolar in vitro antiviral activity. Bioorg Med Chem Lett 2018; 28:3463-3471. [PMID: 30290989 DOI: 10.1016/j.bmcl.2018.09.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/13/2018] [Accepted: 09/17/2018] [Indexed: 01/23/2023]
Abstract
An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1'-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat.
Collapse
Affiliation(s)
- Venkat R Gadhachanda
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States
| | - Kyle J Eastman
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States
| | - Qiuping Wang
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States
| | - Avinash S Phadke
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States
| | - Dharaben Patel
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States
| | - Wengang Yang
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States
| | - Christopher W Marlor
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States
| | - Milind Deshpande
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States
| | - Mingjun Huang
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States
| | - Jason A Wiles
- Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511, United States.
| |
Collapse
|
|
30
|
Abdallah OM, Abdel-Megied AM, Gouda AS. Pharmacokinetic evaluation of daclatasvir and ledipasvir in healthy volunteers using a validated highly sensitive spectrofluorimetric method. LUMINESCENCE 2018; 33:1094-1100. [DOI: 10.1002/bio.3514] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 05/03/2018] [Accepted: 05/13/2018] [Indexed: 01/26/2023]
Affiliation(s)
- Ola M. Abdallah
- Analytical Chemistry Department, Faculty of Pharmacy; Al-Azhar University (Girls); Cairo Egypt
- Pharmaceutical Chemistry Department, Faculty of Pharmacy; Badr University in Cairo (BUC); Badr City Cairo Egypt
| | - Ahmed M. Abdel-Megied
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy and Pharmaceutical Manufacturing; Kafrelsheikh University; Kafrelsheikh City Egypt
| | | |
Collapse
|
|
31
|
Venables BL, Sin N, Wang AX, Sun LQ, Tu Y, Hernandez D, Sheaffer A, Lee M, Dunaj C, Zhai G, Barry D, Friborg J, Yu F, Knipe J, Sandquist J, Falk P, Parker D, Good AC, Rajamani R, McPhee F, Meanwell NA, Scola PM. P3-P4 ureas and reverse carbamates as potent HCV NS3 protease inhibitors: Effective transposition of the P4 hydrogen bond donor. Bioorg Med Chem Lett 2018; 28:1853-1859. [PMID: 29650290 DOI: 10.1016/j.bmcl.2018.04.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 04/02/2018] [Accepted: 04/04/2018] [Indexed: 11/17/2022]
Abstract
A series of tripeptidic acylsulfonamide inhibitors of HCV NS3 protease were prepared that explored structure-activity relationships (SARs) at the P4 position, and their in vitro and in vivo properties were evaluated. Enhanced potency was observed in a series of P4 ureas; however, the PK profiles of these analogues were less than optimal. In an effort to overcome the PK shortcomings, modifications to the P3-P4 junction were made. This included a strategy in which one of the two urea N-H groups was either N-methylated or replaced with an oxygen atom. The former approach provided a series of regioisomeric N-methylated ureas while the latter gave rise to P4 reverse carbamates, both of which retained potent NS3 inhibitory properties while relying upon an alternative H-bond donor topology. Details of the SARs and PK profiles of these analogues are provided.
Collapse
Affiliation(s)
- Brian L Venables
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
| | - Ny Sin
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Alan Xiangdong Wang
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Li-Qiang Sun
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Yong Tu
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Dennis Hernandez
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Amy Sheaffer
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Min Lee
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Cindy Dunaj
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Guangzhi Zhai
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Diana Barry
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Jacques Friborg
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Fei Yu
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Jay Knipe
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Jason Sandquist
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Paul Falk
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Dawn Parker
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Andrew C Good
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Ramkumar Rajamani
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Fiona McPhee
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Nicholas A Meanwell
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Paul M Scola
- Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| |
Collapse
|
|
32
|
Discovery of Beclabuvir: A Potent Allosteric Inhibitor of the Hepatitis C Virus Polymerase. HCV: THE JOURNEY FROM DISCOVERY TO A CURE 2018; 31. [PMCID: PMC7123187 DOI: 10.1007/7355_2018_38] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The discovery of beclabuvir occurred through an iterative series of structure-activity relationship studies directed at the optimization of a novel class of indolobenzazepines. Within this research, a strategic decision to abandon a highly potent but physiochemically problematic series in favor of one of lower molecular weight and potency was key in the realization of the program’s objectives. Subsequent cycles of analog design incorporating progressive conformational constraints successfully addressed off-target liabilities and identified compounds with improved physiochemical profiles. Ultimately, a class of alkyl-bridged piperazine carboxamides was found to be of particular interest, and from this series, beclabuvir was identified as having superior antiviral, safety, and pharmacokinetic properties. The clinical evaluation of beclabuvir in combination with both the NS5A replication complex inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir in a single, fixed-dose formulation (Ximency) resulted in the approval by the Japanese Pharmaceutical and Food Safety Bureau for its use in the treatment of patients infected with genotype 1 HCV.
Collapse
|
|
33
|
Young RJ, Leeson PD. Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations. J Med Chem 2018; 61:6421-6467. [DOI: 10.1021/acs.jmedchem.8b00180] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Robert J. Young
- GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Paul D. Leeson
- Paul Leeson Consulting Ltd., The Malt House, Main Street, Congerstone, Nuneaton, Warwickshire CV13 6LZ, U.K
| |
Collapse
|
|
34
|
Nair AG, Zeng Q, Selyutin O, Rosenblum SB, Jiang Y, Yang DY, Keertikar K, Zhou G, Dwyer M, Kim SH, Shankar B, Yu W, Tong L, Chen L, Mazzola R, Caldwell J, Tang H, Agrawal S, Liu R, Kong R, Ingravallo P, Xia E, Zhai Y, Nomeir A, Asante-Appiah E, Kozlowski JA. MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV. Bioorg Med Chem Lett 2018; 28:1954-1957. [PMID: 29653894 DOI: 10.1016/j.bmcl.2018.03.049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/17/2018] [Accepted: 03/19/2018] [Indexed: 11/29/2022]
Abstract
HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.
Collapse
Affiliation(s)
- Anilkumar G Nair
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
| | - Qingbei Zeng
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Oleg Selyutin
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | | | - Yueheng Jiang
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - De-Yi Yang
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Kerry Keertikar
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Guowei Zhou
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Michael Dwyer
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Seong Heon Kim
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | | | - Wensheng Yu
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Ling Tong
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Lei Chen
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Robert Mazzola
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - John Caldwell
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Haiqun Tang
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Sony Agrawal
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Rong Liu
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Rong Kong
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Paul Ingravallo
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Ellen Xia
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Ying Zhai
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | - Amin Nomeir
- Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
| | | | | |
Collapse
|
|
35
|
Díaz-Eufracio BI, Palomino-Hernández O, Houghten RA, Medina-Franco JL. Exploring the chemical space of peptides for drug discovery: a focus on linear and cyclic penta-peptides. Mol Divers 2018; 22:259-267. [PMID: 29446006 DOI: 10.1007/s11030-018-9812-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 01/23/2018] [Indexed: 10/18/2022]
Abstract
Peptide and peptide-like structures are regaining attention in drug discovery. Previous studies suggest that bioactive peptides have diverse structures and may have physicochemical properties attractive to become hit and lead compounds. However, chemoinformatic studies that characterize such diversity are limited. Herein, we report the physicochemical property profile and chemical space of four synthetic linear and cyclic combinatorial peptide libraries. As a case study, the analysis was focused on penta-peptides. The chemical space of the peptide and N-methylated peptides libraries was compared to compound data sets of pharmaceutical relevance. Results indicated that there is a major overlap in the chemical space of N-methylated cyclic peptides with inhibitors of protein-protein interactions and macrocyclic natural products available for screening. Also, there is an overlap between the chemical space of the synthetic peptides with peptides approved for clinical use (or in clinical trials), and to other approved drugs that are outside the traditional chemical space. Results further support that synthetic penta-peptides are suitable compounds to be used in drug discovery projects.
Collapse
Affiliation(s)
- Bárbara I Díaz-Eufracio
- School of Chemistry, Department of Pharmacy, Universidad Nacional Autónoma de México, Avenida Universidad 3000, 04510, Mexico City, Mexico
| | - Oscar Palomino-Hernández
- School of Chemistry, Department of Pharmacy, Universidad Nacional Autónoma de México, Avenida Universidad 3000, 04510, Mexico City, Mexico
| | - Richard A Houghten
- Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, 34987, USA
| | - José L Medina-Franco
- School of Chemistry, Department of Pharmacy, Universidad Nacional Autónoma de México, Avenida Universidad 3000, 04510, Mexico City, Mexico.
| |
Collapse
|
|
36
|
Design, synthesis and identification of silicon-containing HCV NS5A inhibitors with pan-genotype activity. Eur J Med Chem 2018; 148:95-105. [PMID: 29454920 DOI: 10.1016/j.ejmech.2018.02.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 01/30/2018] [Accepted: 02/09/2018] [Indexed: 01/26/2023]
Abstract
Modification of a HCV NS5A inhibitor, ombitasvir, led to the identification of 10d with improved pan-genotype NS5A inhibition and better pharmacokinetic properties. The key structural changes to ombitasvir include bioisosteric replacement of carbon with silicon atom. Compared with ombitasvir, the activity of anti-HCV genotypes (GT 1 to 6) of 10d is increased to some extent, especially the inhibitory activity against genotype 3a and 6a is increased by more than seven times, and the dog's in vivo pharmacokinetics properties were also superior to ombitasvir. Further drug evaluation showed that 10d was similar to ombitasvir on plasma protein binding and liver distribution profiles, with no cytotoxicity and no inhibitory effect on both CYP 450 and hERG ligand binding. However, permeability assay results indicated that 10d was not the substrate of P-gp or BCRP transporter, which is different from that of ombitasvir. The results of a 14-day repeat-dose toxicity study identified no toxicity with 10d. Our findings in preclinical tests suggest that the silicon-containing compound 10d could be worthy of continued study as a potential drug candidate.
Collapse
|
|
37
|
Abdallah OM, Abdel-Megied AM, Gouda AS. Development and validation of LC-MS/MS method for simultaneous determination of sofosbuvir and daclatasvir in human Plasma: Application to pharmacokinetic study. Biomed Chromatogr 2018; 32:e4186. [PMID: 29314090 DOI: 10.1002/bmc.4186] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 12/13/2017] [Accepted: 12/20/2017] [Indexed: 01/17/2023]
Abstract
A simple and highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method was developed and fully validated for the first time for the simultaneous determination of newly discovered antiviral drugs, namely sofosbuvir (SOF) and daclatasvir (DAC) in human plasma. Tadalafil (TAD) was used as internal standard (IS). SOF, DAC and TAD (IS) were extracted from plasma using liquid-liquid extraction technique with methyl tert-butyl ether. The chromatographic separation was carried out using ZorbaxSB-C18 column (4.6 × 50 mm,5 μm) and 5 mm ammonium formate buffer (pH 3.5)-acetonitrile (50:50, v/v) as mobile phase in an isocratic elution mode pumped at a flow rate 0.7 mL min-1 . The quantitation was performed on API4500 triple quadrupole tandem mass spectrometer with positive electrospray ionization interface in multiple reaction monitoring mode. Validation was applied according to US Food and Drug Administration guidelines for bio-analytical methodswith respect to linearity, precision, accuracy, selectivity, carry-over, stability and dilution integrity. Linearity was obtained over concentration ranges of 0.3-3000 and 3-3000 ng mL-1 for SOF and DAC, respectively, by applying a weighted least-squares linear regression method (1/x2 ). The proposed method could be applied successfully in bioequivalence and/or clinical studies for therapeutic drug monitoring of patients undergoing dual combination therapy as the latter combination proved more efficacious and powerful tool for the complete treatment of hepatitis C genotype 3 within 16 weeks. The suggested method has been applied successfully to pharmacokinetic studies with excellent assay ruggedness and reproducibility.
Collapse
Affiliation(s)
- Ola M Abdallah
- Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University (Girls), Cairo, Egypt.,Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, Egypt
| | - Ahmed M Abdel-Megied
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy and Pharmaceutical Manufacturing, Kafrelsheikh University, Kafrelsheikh City, Egypt
| | | |
Collapse
|
|
38
|
Yi Z, Yuan Z. Aggregation of a hepatitis C virus replicase module induced by ablation of p97/VCP. J Gen Virol 2017; 98:1667-1678. [PMID: 28691899 DOI: 10.1099/jgv.0.000828] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hijacking host membranes to assemble a membrane-associated viral replicase is a hallmark of almost all positive-strand RNA viruses. However, how the virus co-opts host factors to facilitate this energy-unfavourable process is incompletely understood. In a previous study, using hepatitis C virus (HCV) as a model and employing affinity purification of the viral replicase, we identified a valosin-containing protein (p97/VCP), a member of the ATPases associated with diverse cellular activities (AAA+ ATPase family), as a viral replicase-associated host factor. It is required for viral replication, depending on its ATPase activity. In this study, we used VCP pharmacological inhibitors and short hairpin (sh) RNA-mediated knockdown to ablate VCP function and then dissected the roles of VCP in viral replicase assembly in an HCV subgenomic replicon system and a viral replicase assembly surrogate system. Ablation of VCP specifically resulted in the pronounced formation of an SDS-resistant aggregation of HCV NS5A and the reduction of hyperphosphorylation of NS5A. The NS5A dimerization domain was indispensable for aggregation and the NS5A disordered regions also contributed to a lesser extent. The reduction of the hyperphosphorylation of NS5A coincided with the aggregation of NS5A. We propose that HCV may co-opt VCP to disaggregate an aggregation-prone replicase module to facilitate its replicase assembly.
Collapse
Affiliation(s)
- Zhigang Yi
- Key Laboratory of Medical Molecular Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Zhenghong Yuan
- Institutes of Medical Microbiology and Biomedical Sciences, Fudan University, Shanghai, PR China.,Key Laboratory of Medical Molecular Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, PR China
| |
Collapse
|
|
39
|
Eastman KJ, Parcella K, Yeung KS, Grant-Young KA, Zhu J, Wang T, Zhang Z, Yin Z, Beno BR, Sheriff S, Kish K, Tredup J, Jardel AG, Halan V, Ghosh K, Parker D, Mosure K, Fang H, Wang YK, Lemm J, Zhuo X, Hanumegowda U, Rigat K, Donoso M, Tuttle M, Zvyaga T, Haarhoff Z, Meanwell NA, Soars MG, Roberts SB, Kadow JF. The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase. MEDCHEMCOMM 2017; 8:796-806. [PMID: 30108798 PMCID: PMC6072320 DOI: 10.1039/c6md00636a] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 01/20/2017] [Indexed: 11/21/2022]
Abstract
The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase via binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 (43) as a preclinical candidate.
Collapse
Affiliation(s)
- Kyle J Eastman
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Kyle Parcella
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Kap-Sun Yeung
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Katharine A Grant-Young
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Juliang Zhu
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Tao Wang
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Zhongxing Zhang
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Zhiwei Yin
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Brett R Beno
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Steven Sheriff
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Kevin Kish
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Jeffrey Tredup
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Adam G Jardel
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Vivek Halan
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Kaushik Ghosh
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Dawn Parker
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Kathy Mosure
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Hua Fang
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Ying-Kai Wang
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Julie Lemm
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Xiaoliang Zhuo
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Umesh Hanumegowda
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Karen Rigat
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Maria Donoso
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Maria Tuttle
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Tatyana Zvyaga
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Zuzana Haarhoff
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Nicholas A Meanwell
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Matthew G Soars
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - Susan B Roberts
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| | - John F Kadow
- Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA .
| |
Collapse
|
|
40
|
McGowan DC, Khamlichi MD, De Groot A, Pauwels F, Delouvroy F, Van Emelen K, Simmen K, Raboisson P. Synthesis and evaluation of novel HCV replication inhibitors. Mol Divers 2017; 21:475-481. [PMID: 28293834 DOI: 10.1007/s11030-017-9733-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/20/2017] [Indexed: 12/15/2022]
Abstract
Direct acting antiviral agents to cure hepatitis C virus (HCV) infection has emerged as the gold standard therapy. Along with protease inhibitors, nucleoside polymerase inhibitors and non-nucleoside polymerase inhibitors, the inhibition of NS5a has proved to be an effective way to treat HCV patients. Here we report on novel HCV NS5a inhibitors which were synthesized and evaluated in the HCV replicon assay. A series of inhibitors were formed by a cycloaddition reaction in parallel to establish new leads and explore the effects of unsymmetrical cap substitution. This led to the identification of several triazoles with picomolar potency in vitro against hepatitis C virus.
Collapse
Affiliation(s)
- David C McGowan
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium.
| | - Mourad D Khamlichi
- Villapharma Research, Parque Tecnológico de Fuente Álamo, Ctra. El Estrecho-Lobosillo, Km. 2,5- Av. Azul, 30320, Fuente Álamo de Murcia, Murcia, Spain
| | - Alex De Groot
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Frederik Pauwels
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Frédéric Delouvroy
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Kristof Van Emelen
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Kenneth Simmen
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Pierre Raboisson
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| |
Collapse
|
|
41
|
Nannetti G, Messa L, Celegato M, Pagni S, Basso M, Parisi SG, Palù G, Loregian A. Development and validation of a simple and robust HPLC method with UV detection for quantification of the hepatitis C virus inhibitor daclatasvir in human plasma. J Pharm Biomed Anal 2017; 134:275-281. [DOI: 10.1016/j.jpba.2016.11.032] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 11/07/2016] [Accepted: 11/13/2016] [Indexed: 11/16/2022]
|
|
42
|
Moore TO, Paradowski M, Ward SE. An atom-efficient and convergent approach to the preparation of NS5A inhibitors by C-H activation. Org Biomol Chem 2016; 14:3307-13. [PMID: 26936019 DOI: 10.1039/c6ob00340k] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A novel approach of the convergent functionalisation of aryl dibromides to form NS5A type inhibitors using C-H activation is reported. The focus of investigation was to reduce the formation of homodimeric side product, as well as to investigate the scope of different aryl dibromides that were tolerated under the reaction conditions. The C-H activation methodology was found to give a viable synthetic route to NS5A inhibitors, with late stage functionalisation of the core portion of the molecule, albeit with some chemical functionalities not tolerated.
Collapse
Affiliation(s)
- Thomas O Moore
- Sussex Drug Discovery Centre, University of Sussex, Brighton, England BN1 9QJ, UK.
| | - Michael Paradowski
- Sussex Drug Discovery Centre, University of Sussex, Brighton, England BN1 9QJ, UK.
| | - Simon E Ward
- Sussex Drug Discovery Centre, University of Sussex, Brighton, England BN1 9QJ, UK.
| |
Collapse
|
|
43
|
Mibu N, Yokomizo K, Murakami K, Ono Y, Ishimaru M, Otsubo M, Inao H, Ono Y, Zhou JR, Sumoto K. Antiviral Activity and Molecular Geometry of Some New Symmetrical Tris(aminoalkyl)amine Derivatives. Chem Pharm Bull (Tokyo) 2016; 64:1769-1780. [PMID: 27904085 DOI: 10.1248/cpb.c16-00682] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We report the preparation of new tripodal receptor-type C3- and CS-symmetrical molecules constructed on a tris(2-aminoethyl)amine (TAEA) template. Both the anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity of synthesized receptor-type derivatives were evaluated in order to find a characteristic structural feature for these bioactivities of compounds. Among the compounds of synthesized symmetrical TAEA-related derivatives, compound 13k showed high anti-HSV-1 activity (50% effective concentration (EC50)=16.7 µM) and low cytotoxicity (50% cytotoxic concentration (CC50)=>200 µM). The presence of a hydrogen bond donor proton in the molecule is thought to be an important structural factor for expressing potential anti-HSV-1 activities.
Collapse
Affiliation(s)
- Nobuko Mibu
- Faculty of Pharmaceutical Sciences, Fukuoka University
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Tong L, Yu W, Chen L, Selyutin O, Dwyer MP, Nair AG, Mazzola R, Kim JH, Sha D, Yin J, Ruck RT, Davies IW, Hu B, Zhong B, Hao J, Ji T, Zan S, Liu R, Agrawal S, Xia E, Curry S, McMonagle P, Bystol K, Lahser F, Carr D, Rokosz L, Ingravallo P, Chen S, Feng KI, Cartwright M, Asante-Appiah E, Kozlowski JA. Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms. J Med Chem 2016; 60:290-306. [PMID: 27808515 DOI: 10.1021/acs.jmedchem.6b01310] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Bin Hu
- Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China
| | - Bin Zhong
- Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China
| | - Jinglai Hao
- Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China
| | - Tao Ji
- Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China
| | - Shuai Zan
- Department of Medicinal Chemistry, WuXi AppTec , Shanghai, 200131, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Discovery of ravidasvir (PPI-668) as a potent pan-genotypic HCV NS5A inhibitor. Bioorg Med Chem Lett 2016; 26:4508-4512. [DOI: 10.1016/j.bmcl.2016.07.066] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 07/25/2016] [Accepted: 07/27/2016] [Indexed: 12/17/2022]
|
|
46
|
Meanwell NA. 2015 Philip S. Portoghese Medicinal Chemistry Lectureship. Curing Hepatitis C Virus Infection with Direct-Acting Antiviral Agents: The Arc of a Medicinal Chemistry Triumph. J Med Chem 2016; 59:7311-51. [PMID: 27501244 DOI: 10.1021/acs.jmedchem.6b00915] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The development of direct-acting antiviral agents that can cure a chronic hepatitis C virus (HCV) infection after 8-12 weeks of daily, well-tolerated therapy has revolutionized the treatment of this insidious disease. In this article, three of Bristol-Myers Squibb's HCV programs are summarized, each of which produced a clinical candidate: the NS3 protease inhibitor asunaprevir (64), marketed as Sunvepra, the NS5A replication complex inhibitor daclatasvir (117), marketed as Daklinza, and the allosteric NS5B polymerase inhibitor beclabuvir (142), which is in late stage clinical studies. A clinical study with 64 and 117 established for the first time that a chronic HCV infection could be cured by treatment with direct-acting antiviral agents alone in the absence of interferon. The development of small molecule HCV therapeutics, designed by medicinal chemists, has been hailed as "the arc of a medical triumph" but may equally well be described as "the arc of a medicinal chemistry triumph".
Collapse
Affiliation(s)
- Nicholas A Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research & Development , Wallingford, Connecticut 06492, United States
| |
Collapse
|
|
47
|
Affiliation(s)
- David L. Hughes
- Cidara Therapeutics, 6310 Nancy Ridge Dr., Suite 101, San Diego, California 92121, United States
| |
Collapse
|
|
48
|
Dwyer MP, Keertikar KM, Chen L, Tong L, Selyutin O, Nair AG, Yu W, Zhou G, Lavey BJ, Yang DY, Wong M, Kim SH, Coburn CA, Rosenblum SB, Zeng Q, Jiang Y, Shankar BB, Rizvi R, Nomeir AA, Liu R, Agrawal S, Xia E, Kong R, Zhai Y, Ingravallo P, Asante-Appiah E, Kozlowski JA. Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors. Bioorg Med Chem Lett 2016; 26:4106-11. [PMID: 27423481 DOI: 10.1016/j.bmcl.2016.06.063] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/23/2016] [Accepted: 06/24/2016] [Indexed: 01/25/2023]
Abstract
A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.
Collapse
Affiliation(s)
- Michael P Dwyer
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
| | - Kerry M Keertikar
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Lei Chen
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Ling Tong
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Oleg Selyutin
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Anilkumar G Nair
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Wensheng Yu
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Guowei Zhou
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Brian J Lavey
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - De-Yi Yang
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Michael Wong
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Seong Heon Kim
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Craig A Coburn
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Stuart B Rosenblum
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Qingbei Zeng
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Yueheng Jiang
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Bandarpalle B Shankar
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Razia Rizvi
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Amin A Nomeir
- Drug Metabolism, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Rong Liu
- Discovery Biology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Sony Agrawal
- Discovery Biology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Ellen Xia
- Discovery Biology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Rong Kong
- Discovery Biology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Ying Zhai
- Discovery Biology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Paul Ingravallo
- Discovery Biology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Ernest Asante-Appiah
- Discovery Biology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| | - Joseph A Kozlowski
- Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, USA
| |
Collapse
|
|
49
|
Abstract
Antiviral therapeutics with profiles of high potency, low resistance, panserotype, and low toxicity remain challenging, and obtaining such agents continues to be an active area of therapeutic development. Due to their unique three-dimensional structural features, spirooxindoles have been identified as privileged chemotypes for antiviral drug development. Among them, spiro-pyrazolopyridone oxindoles have been recently reported as potent inhibitors of dengue virus NS4B, leading to the discovery of an orally bioavailable preclinical candidate (R)-44 with excellent in vivo efficacy in a dengue viremia mouse model. This review highlights recent advances in the development of biologically active spirooxindoles for their antiviral potential, primarily focusing on the structure-activity relationships (SARs) and modes of action, as well as future directions to achieve more potent analogues toward a viable antiviral therapy.
Collapse
Affiliation(s)
- Na Ye
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, United States
| | - Haiying Chen
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, United States
| | - Eric A. Wold
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, United States
| | - Pei-Yong Shi
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, United States
- Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, United States
- Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, United States
| | - Jia Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, United States
- Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, United States
| |
Collapse
|
|
50
|
Li W, Zhao W, Liu X, Huang X, Lopez OD, Leet JE, Fancher RM, Nguyen V, Goodrich J, Easter J, Hong Y, Caceres-Cortes J, Chang SY, Ma L, Belema M, Hamann LG, Gao M, Zhu M, Shu YZ, Humphreys WG, Johnson BM. Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine δ-Oxidation and Rearrangement. Drug Metab Dispos 2016; 44:809-20. [PMID: 27029743 DOI: 10.1124/dmd.115.068866] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 03/28/2016] [Indexed: 01/05/2023] Open
Abstract
Daclatasvir is a first-in-class, potent, and selective inhibitor of the hepatitis C virus nonstructural protein 5A replication complex. In support of nonclinical studies during discovery and exploratory development, liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance were used in connection with synthetic and radiosynthetic approaches to investigate the biotransformation of daclatasvir in vitro and in cynomolgus monkeys, dogs, mice, and rats. The results of these studies indicated that disposition of daclatasvir was accomplished mainly by the release of unchanged daclatasvir into bile and feces and, secondarily, by oxidative metabolism. Cytochrome P450s were the main enzymes involved in the metabolism of daclatasvir. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. Despite robust formation of the resulting metabolite in multiple systems, rates of covalent binding to protein associated with metabolism of daclatasvir were modest (55.2-67.8 pmol/mg/h) in nicotinamide adenine dinucleotide phosphate (reduced form)-supplemented liver microsomes (human, monkey, rat), suggesting that intramolecular rearrangement was favored over intermolecular binding in the formation of this metabolite. This biotransformation profile supported the continued development of daclatasvir, which is now marketed for the treatment of chronic hepatitis C virus infection.
Collapse
Affiliation(s)
- Wenying Li
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Weiping Zhao
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Xiaohong Liu
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Xiaohua Huang
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Omar D Lopez
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - John E Leet
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - R Marcus Fancher
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Van Nguyen
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Jason Goodrich
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - John Easter
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Yang Hong
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Janet Caceres-Cortes
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Shu Y Chang
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Li Ma
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Makonen Belema
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Lawrence G Hamann
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Min Gao
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Mingshe Zhu
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Yue-Zhong Shu
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - W Griffith Humphreys
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| | - Benjamin M Johnson
- Departments of Pharmaceutical Candidate Optimization (W.L., W.Z., X.L., X.H., R.M.F., J.C.-C., S.Y.C., L.M., M.Z., Y.-Z.S., W.G.H., B.M.J.), Synthesis and Analysis Technology Team (J.E.L.), Virology (M.G.), and Chemistry (O.D.L., V.N., J.G., J.E., Y.H., M.B., L.G.H.), Bristol-Myers Squibb Company, Wallingford, Connecticut
| |
Collapse
|