RESUMO
The design, synthesis and biological activity of new thrombin inhibitors with a pyridinone or pyrazinone core and different heterobicyclic P(1) arginine side-chain mimetics are described. The arginine side-chain mimetics used in this study are (+/-)-4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine and both enantiomers thereof, (+/-)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine and the corresponding R enantiomer. Compound 25, the most potent in the series of pyrazinone inhibitors, exhibited a K(i) of 41 nM in vitro and high selectivity against trypsin and factor Xa.
Assuntos
Antitrombinas/química , Antitrombinas/farmacologia , Arginina/química , Arginina/farmacologia , Materiais Biomiméticos/farmacologia , Pirazinas/química , Piridonas/química , Piridonas/uso terapêutico , Materiais Biomiméticos/química , Concentração de Íons de Hidrogênio , EstereoisomerismoRESUMO
Optimization of lead compounds 1 and 2 resulted in novel, selective, and potent thrombin inhibitors incorporating weakly basic heterobicyclic P(1)-arginine mimetics. The design, synthesis, and biological activity of racemic thrombin inhibitors 17-29 and enantiomerically pure thrombin inhibitors 30-33 are described. The arginine side-chain mimetics used in this study are 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, 4,5,6,7-tetrahydro-2H-indazole, and 2-imino-4,5,6,7-tetrahydro-1,3-benzothiazol-3(2H)-ylamine.
Assuntos
Arginina/química , Fibrinolíticos/química , Inibidores de Serina Proteinase/química , Trombina/antagonistas & inibidores , Arginina/farmacologia , Fibrinolíticos/farmacologia , Humanos , Inibidores de Serina Proteinase/farmacologia , Trombina/metabolismoRESUMO
Novel, highly selective and potent thrombin inhibitors were identified as a result of combing the 3-benzylsulfonylamino-2-pyridinone acetamide P(2)-P(3) surrogate with weakly basic partially saturated heterobicyclic P(1)-arginine mimetics 1-8. The design, synthesis, biological activity, and the binding modes of non-covalent thrombin inhibitors featuring P(1)-4,5,6,7-tetrahydroindazole, 5,6,7,8-tetrahydroquinazoline, and 4,5,6,7-tetrahydrobenzothiazole moieties are described.