Potent, Orally Bioavailable Calcitonin Gene-Related Peptide Receptor Antagonists for the Treatment of Migraine: Discovery of N -[(3 R ,6 S )-6-(2,3-Difluorophenyl)-2-oxo-1- (2,2,2-trifluoroethyl)azepan-3-yl]-4- (2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin- 1-yl)piperidine-1-carboxamide (MK-0974)
Journal of Medicinal Chemistry2007Vol. 50(23), pp. 5564–5567
Citations Over TimeTop 10% of 2007 papers
Daniel V. Paone, Anthony W. Shaw, Diem N. Nguyen, Christopher S. Burgey, James Z. Deng, Stefanie A. Kane, Kenneth S. Koblan, Christopher Salvatore, Scott D. Mosser, Victor K. Johnston, Bradley K. Wong, Cynthia Miller‐Stein, James C. Hershey, Samuel Graham, Joseph P. Vacca, Theresa M. Williams
Abstract
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 phenylimidazolinone 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).
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