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: Chaturvedula PV; Department of Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA. Prasad.Chaturvedula@bms.com, Mercer SE, Pin SS, Thalody G, Xu C, Conway CM, Keavy D, Signor L, Cantor GH, Mathias N, Moench P, Denton R, Macci R, Schartman R, Whiterock V, Davis C, Macor JE, Dubowchik GM
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Jun 01; Vol. 23 (11), pp. 3157-61. Date of Electronic Publication: 2013 Apr 12.
DOI: 10.1016/j.bmcl.2013.04.012
Abstrakt: 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.
(Copyright © 2013 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: