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

  • J Med Chem. 2012 Dec 13;55(23):10644-51. doi: 10.1021/jm3013147.
Guanglin Luo  1 ,  Ling Chen ,  Charles M Conway ,  Rex Denton ,  Deborah Keavy ,  Laura Signor ,  Walter Kostich ,  Kimberley A Lentz ,  Kenneth S Santone ,  Richard Schartman ,  Marc Browning ,  Gary Tong ,  John G Houston ,  Gene M Dubowchik ,  John E Macor
Affiliations
  • 1. Molecular Sciences and Candidate Optimization, Disease Sciences and Biologics, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States. [email protected]
PMID: 23153230 DOI: 10.1021/jm3013147
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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