Novel pyrazinone and pyridinone thrombin inhibitors incorporating weakly basic heterobicyclic P1-arginine mimetics

The design, synthesis and biological activity of new thrombin inhibitors with a pyridinone or pyrazinone core and different heterobicyclic P1 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 Ki of 41 nM in vitro and high selectivity against trypsin and factor Xa.