Copyright ©The Author(s) 2016.
World J Gastroenterol. Dec 21, 2016; 22(47): 10275-10286
Published online Dec 21, 2016. doi: 10.3748/wjg.v22.i47.10275
Table 1 Serine protease inhibitors (mammalian): examples of clinical applications in different organ systems
CategoryIndicationSerine protease inhibitor (target)StatusRef.
CardiovascularACSBivalirudin (thrombin)Approved[73]
AFRivaroxaban (factor Xa)Approved[74]
Edoxaban (factor Xa)Approved[75]
VTEDabigatran (thrombin)Approved[76]
DermatologyHerpes zosterArgatroban (thrombin)Clinical - phase II[77]
Oral leukoplakiaBBIC (broad specificity)Clinical - phase II[78]
HematologyHeparin-induced thrombocytopeniaArgatroban (thrombin)Approved[79]
Fondaparinux (factor Xa)Approved
OncologyPancreatic cancer: CTxUpamostat (uPA)Clinical - phase II[80]
Nafamostat mesilate (broad specificity)Clinical - phase II[81]
Lung cancer: RTxUlinastatin (broad specificity)Clinical - phase unknown[82]
Colorectal cancer: CTxTalabostat (fibroblast activating protein)Clinical - phase II[83]
Esophageal cancer: SxUlinastatin (broad specificity)Clinical - phase unknown[84]
PneumologyAsthmaAPC 366 (mast cell tryptase)Clinical - phase II[85]
α1 antitrypsin deficiencyα1 antitrypsin (broad specificity)Approved[86]
Cystic fibrosisα1 antitrypsin (broad specificity)Clinical - phase II[87]
EndocrinologyDiabetesGliptins (DPP-IV)1Approved[88]
SurgeryNAAprotinin (broad specificity)Approved[89]
Gabexate mesilate (broad specificity)Clinical - phase III[90]
Nafamostat mesilate (broad specificity)Clinical - phase IV[91]
Sivelestat (neutrophil elastase)Clinical - phase unknown[92]
Table 2 Preclinical studies investigating the effects of protease-activated receptor-targeting molecules on visceral hypersensitivity
PARAgonist/antagonistSpecies (hypersensitivity model)Study typeEffectRef.
PAR-1Agonist (thrombin, TFLLR-NH2)Rat (carrageenan)In vivo↓ hyperalgesia[56]
PAR-1Agonist (TFLLR-NH2)Mice (capsaicin)In vivo↓ hyperalgesia[55]
PAR-2Agonist (SLIGRL-NH2)Mice (PAR2-agonist)In vivo↑ hyperalgesia[59]
PAR-2Agonist (SLIGRL-NH2, trypsin)Rat (PAR2-agonist)In vivo↑ hyperalgesia[60]
PAR-2Agonist (SL-NH2, trypsin, typtase)Guinea pig submucosal neurons (PAR2-agonist)Ex vivo↑ neuron excitability[61]
PAR-2Agonist (SLIGRL-NH2, Tc-NH2, trypsin, tryptase)Mice, rat (PAR2-agonist)KO↑ hyperalgesia, absent in KO[62]
PAR-2Agonist (2-furoyl-LIGRL-NH2)Mice (capsaicin)KO↑ hyperalgesia, absent in KO[63]
PAR-2Antagonist (ENMD-1068)Mice (IBS-supernatant)KO↓ hypersensitivity, absent in KO[41]
PAR-2/Mice DRG (IBS-D supernatant)KO↑ neuron excitability, absent in KO[64]
PAR-4Agonist (PAR-4-AP, Cat-G)Mice (IBS-D supernatant)In vivo↓ hypersensitivity[49]
PAR-4Agonist (AYPGKF-NH2)Mice (PAR2-agonist, TRPV4-agonist)In vivo↓ hypersensitivity[57]
Table 3 Serine protease inhibitors investigated in experimental visceral hypersensitivity models
Inhibitor nameTarget(s)Ref.
AprotininChymotrypsin, elastase, KLK, plasmin, PA, trypsin, urokinase, XIIa[49]
Bowman-Birk inhibitorChymotrypsin, trypsin[70,71]
Camostat mesilate (FOY-305)Trypsin, matriptase, prostasin, plasmin, tPA, uPA, Xa, IXa, thrombin, tissue factor, complement factors, tryptase, HNE, KLK[68,69]
Cathepsin-G inhibitorCathepsin G[49]
Nafamostat mesilate (FUT-175)Tryptase, trypsin, C1r, C1s, thrombin, kallikrein, plasmin[37,65-67]
UAMC-0050Tryptase, matriptase, KLK4, KLK8, uPA[66,67,93]
Soybean trypsin inhibitor (SBTI)Trypsin, chymotrypsin, plasmin, kallikrein, Xa[49]