Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): A potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery |
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| Authors: | Prasad V. Chaturvedula Stephen E. Mercer Sokhom S. Pin George Thalody Cen Xu Charlie M. Conway Deborah Keavy Laura Signor Glenn H. Cantor Neil Mathias Paul Moench Rex Denton Robert Macci Richard Schartman Valerie Whiterock Carl Davis John E. Macor Gene M. Dubowchik |
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| Affiliation: | 1. Department of Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA;2. Department of Neuroscience Discovery Biology, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA |
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| Abstract: | ![]()
Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow. |
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| Keywords: | CGRP receptor antagonist for intranasal delivery |
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