Structure-Based
Design of Macrocyclic Coagulation Factor VIIa Inhibitors
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Abstract
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 <i>K</i><sub>i</sub> = 1.6 nM, excellent selectivity against a
panel of seven serine proteases, and FVII-deficient prothrombin time
EC<sub>2<i>x</i></sub> = 1.2 μM. Discovery of this
potent, selective macrocyclic scaffold opens new possibilities for
the development of orally bioavailable FVIIa inhibitors
