Novel thrombin inhibitors incorporating non-basic partially saturated heterobicyclic P1-Arginine mimetics

The design, synthesis and biological activity of non-covalent thrombin inhibitors incorporating 4,5,6,7-tetrahydroindazole, 2-methyl-4,5,6,7-tetrahydroindazole, 4,5,6,7-tetrahydroisoindole, 5,6,7,8-tetrahydroquinazoline and 5,6,7,8-tetrahydroquinazolin-2-amine as novel, partially saturated, heterobicyclic P1-arginine side-chain mimetics is described. The binding mode of the most potent candidate in the series co-crystallized with human α-thrombin, which exhibited an in vitro Ki of 140 nM and more that 478-fold selectivity against trypsin, is discussed.