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

Autor: John E. Macor, Chaturvedula Prasad, Rex Denton, Gene M. Dubowchik, Paul Moench, Valerie J. Whiterock, Charlie M. Conway, Cen Xu, Neil Mathias, Glenn H. Cantor, Robert Macci, Richard Schartman, Laura J. Signor, Stephen E. Mercer, George Thalody, Carl D. Davis, Deborah Keavy, Sokhom S. Pin
Rok vydání: 2013
Předmět:
Zdroj: Bioorganic & Medicinal Chemistry Letters. 23:3157-3161
ISSN: 0960-894X
Popis: 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.
Databáze: OpenAIRE