Inhibitors of the tissue factor-Factor VIIa serine protease complex (TF-FVIIa) have shown strong antithrombotic efficacy in animal models with minimal bleeding liability, suggesting the TF-FVIIa complex is an important therapeutic target for the treatment of thrombotic disorders. We have discovered a macrocyclic, phenylglycine amide-based inhibitor of TF-FVIIa. Further optimization of this chemotype was complicated by the observation of atropisomerism upon substitution of the P2 phenyl group of that macrocycle. Based upon NMR studies of the exchange of these atropisomers and molecular modeling of stabilizing strategies, we identified linker substitution that rigidified the desired atropisomer and significantly improved potency.

Design and synthesis of conformationally rigid macrocyclic tissue factor-factor VIIa inhibitors

245th National Meeting (2013)

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