Inhibitors of the clotting cascade serine protease Factor VIIa (FVIIa) have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. However, discovery of orally active FVIIa inhibitors has been largely unsuccessful because high affinity binding has required a basic group to bind Asp189 in the S1 pocket, limiting permeability. In an attempt to discover permeable, neutral P1 groups, we undertook a multidisciplinary fragment screening effort, involving virtual screening, high concentration enzyme assays, NMR binding studies and crystallography. A dihydroisoquinolinone P1 fragment discovered in this effort was spliced into a phenylglycine FVIIa inhibitor chemotype to produce a neutral, selective, and permeable FVIIa inhibitor. Subsequent optimization of the P1 region guided by fragment screening results led to a novel series of  FVIIa inhibitors with low nanomolar potency.

Discovery of potent neutral factor VIIa inhibitors

244th National Meeting (2012)

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