Atropisomer Control in Macrocyclic Factor VIIa Inhibitors

Incorporation of a methyl group onto
a macrocyclic FVIIa inhibitor
improves potency 10-fold but is accompanied by atropisomerism due
to restricted bond rotation in the macrocyclic structure, as demonstrated
by NMR studies. We designed a conformational constraint favoring the
desired atropisomer in which this methyl group interacts with the
S2 pocket of FVIIa. A macrocyclic inhibitor incorporating this constraint
was prepared and demonstrated by NMR to reside predominantly in the
desired conformation. This modification improved potency 180-fold
relative to the unsubstituted, racemic macrocycle and improved selectivity.
An X-ray crystal structure of a closely related analogue in the FVIIa
active site was obtained and matches the NMR and modeled conformations,
confirming that this conformational constraint does indeed direct
the methyl group into the S2 pocket as designed. The resulting rationally
designed, conformationally stable template enables further optimization
of these macrocyclic inhibitors.