Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Based on a zwitterionic phenylglycine acyl sulfonamide, a series of phenylglycine benzamide TF-FVIIa inhibitors was designed to improve permeability and oral bioavailability. Optimization of the benzamide and conformational constraint with a pyrrolidine ring lead to potent TF-FVIIa inhibitors with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring resulted in a series of highly potent, selective and efficacious TF-FVIIa inhibitors. The pyrrolidine acid TF-FVIIa inhibitors showed high clearance and short t1/2 in dog PK studies.

Design and synthesis of phenylpyrrolidine phenylglycineamides as highly potent and selective TF-FVIIa inhibitors

244th National Meeting (2012)

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