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. Epub 2012 Nov 15.

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.

MeSH terms

  • Administration, Oral
  • Calcitonin Gene-Related Peptide / antagonists & inhibitors*
  • Clinical Trials as Topic
  • Drug Discovery*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Migraine Disorders / drug therapy*
  • Piperidines / chemistry*
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*

Substances

  • Piperidines
  • Pyridines
  • rimegepant sulfate
  • Calcitonin Gene-Related Peptide