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

2012; American Chemical Society; Volume: 3; Issue: 4 Linguagem: Inglês

10.1021/ml300021s

1948-5875

Guanglin Luo, Ling Chen, Charles M. Conway, Rex Denton, Deborah Keavy, Michael Gulianello, Yanling Huang, Walter A. Kostich, Kimberley A. Lentz, Stephen E. Mercer, Richard Schartman, Laura J. Signor, Marc Browning, John E. Macor, Gene M. Dubowchik,

Trigeminal Neuralgia and Treatments

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.