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

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

doi:10.1016/j.bmcl.2013.04.012

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

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3157-61. doi: 10.1016/j.bmcl.2013.04.012. Epub 2013 Apr 12.

Authors

Prasad V Chaturvedula¹, 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

Affiliation

¹ Department of Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA. Prasad.Chaturvedula@bms.com

PMID: 23632269
DOI: 10.1016/j.bmcl.2013.04.012

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.

MeSH terms

Administration, Intranasal
Amides / chemistry*
Amides / pharmacology
Amides / therapeutic use
Animals
Caco-2 Cells
Calcitonin Gene-Related Peptide Receptor Antagonists*
Callithrix
Coronary Vessels / drug effects
Drug Evaluation, Preclinical
Face / blood supply
Humans
Indazoles / chemistry*
Indazoles / pharmacology
Indazoles / therapeutic use
Migraine Disorders / drug therapy
Quinolones / chemistry*
Quinolones / pharmacology
Quinolones / therapeutic use
Rabbits
Rats
Receptors, Calcitonin Gene-Related Peptide / metabolism
Respiratory Mucosa / drug effects
Respiratory Mucosa / pathology

Substances

Amides
Calcitonin Gene-Related Peptide Receptor Antagonists
Indazoles
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
Quinolones
Receptors, Calcitonin Gene-Related Peptide