Discovery of BMS-846372, a Potent and Orally Active Human CGRP Receptor Antagonist for the Treatment of Migraine

  • ACS Med Chem Lett. 2012 Feb 27;3(4):337-41. doi: 10.1021/ml300021s.
Guanglin Luo  1 ,  Ling Chen  1 ,  Charles M Conway  1 ,  Rex Denton  1 ,  Deborah Keavy  1 ,  Michael Gulianello  1 ,  Yanling Huang  1 ,  Walter Kostich  1 ,  Kimberley A Lentz  1 ,  Stephen E Mercer  1 ,  Richard Schartman  1 ,  Laura Signor  1 ,  Marc Browning  1 ,  John E Macor  1 ,  Gene M Dubowchik  1
Affiliations
  • 1. Molecular Sciences and Candidate Optimization, Neuroscience Biology, Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
PMID: 24900474 DOI: 10.1021/ml300021s
Abstract

Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically shown to be effective in the treatment of migraine, but identification of potent and orally bioavailable compounds has been challenging. Herein, we describe the conceptualization, synthesis, and preclinical characterization of a potent, orally active CGRP Receptor Antagonist 5 (BMS-846372). Compound 5 has good oral bioavailability in rat, dog, and cynomolgus monkeys and overall attractive preclinical properties including strong (>50% inhibition) exposure-dependent in vivo efficacy in a marmoset migraine model.

Keywords
CGRP; CGRP receptor; antagonist; migraine.
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