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Novel pyrazinone and pyridinone thrombin inhibitors incorporating weakly basic heterobicyclic P(1)-arginine mimetics
Andreja Kranjc1, Lucija Peterlin Masic, Sebastjan Reven
1Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Abstract:
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.
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