Inhibitors of the tissue factor-Factor VIIa complex have demonstrated excellent efficacy and minimal bleeding liability in preclinical antithrombotic models.  We have previously reported macrocyclic inhibitors of FVIIa based on a 16-membered, para-linked phenylglycine core.  Herein we describe the design and optimization of a novel series of macrocyclic FVIIa inhibitors based on a phenylglycine core.  Molecular modeling and crystallography were utilized to optimize the size, constitution, and substitution of the macrocyclic ring.  The inhibitors were further improved to single digit nanomolar potency, with good clotting activity and good selectivity.

Design and optimization of novel macrocyclic FVIIa inhibitors

246th National Meeting (2013)

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