Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors

摘要

Inhibitors of Factor Vila (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the Si binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the Si pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this PI binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.