ACS Medicinal Chemistry Letters 2012-04-12

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

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

文献索引：ACS Med. Chem. Lett. 3(4) , 337-41, (2012)

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摘要

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.