Discovery of (5S,6S,9R)-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): An Oral Calcitonin Gene-Related Peptide (CGRP) Antagonist in Clinical Trials for Treating Migraine
Journal of Medicinal Chemistry2012Vol. 55(23), pp. 10644–10651
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Guanglin Luo, Ling Chen, Charles M. Conway, Rex Denton, Deborah Keavy, Laura J. Signor, Walter A. Kostich, Kimberley A. Lentz, Kenneth S. Santone, Richard Schartman, Marc Browning, Gary Tong, John G. Houston, Gene M. Dubowchik, John E. Macor
Abstract
Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.
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