Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors

On the basis of a crystal structure
of a phenylpyrrolidine lead and subsequent molecular modeling results,
we designed and synthesized a novel series of macrocyclic FVIIa inhibitors.
The optimal 16-membered macrocycle was 60-fold more potent than an
acyclic analog. Further potency optimization by incorporation of P1′
alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa Ki = 1.6 nM, excellent selectivity against a
panel of seven serine proteases, and FVII-deficient prothrombin time
EC2x = 1.2 μM. Discovery of this
potent, selective macrocyclic scaffold opens new possibilities for
the development of orally bioavailable FVIIa inhibitors.