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

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.

SUBMITTER: Luo G 

PROVIDER: S-EPMC4025799 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other

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

Luo Guanglin G   Chen Ling L   Conway Charles M CM   Denton Rex R   Keavy Deborah D   Gulianello Michael M   Huang Yanling Y   Kostich Walter W   Lentz Kimberley A KA   Mercer Stephen E SE   Schartman Richard R   Signor Laura L   Browning Marc M   Macor John E JE   Dubowchik Gene M GM  

ACS medicinal chemistry letters 20120227 4

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 incl  ...[more]

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