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

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

ACS medicinal chemistry letters (2012-04-12)

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

PMID24900474

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.