Potent,Orally Bioavailable Calcitonin Gene-Related Peptide Receptor Antagonists for the Treatment of Migraine:Discovery of N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl

摘要

Calcitonin gene-related peptide(CGRP)has been implicated in the pathogenesis of migraine.Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a(3R)-amino-(6S)-phenylcaprolactam core.Replacement of the phenyl-imidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts.Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group,and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities,ultimately leading to clinical candidate 38(MK-0974).