Carbamates as potent calcitonin gene-related peptide antagonists with improved solution stability

Andrew P Degnan; Charles M Conway; Richard A Dalterio; Robert Macci; Stephen E Mercer; Richard Schartman; Cen Xu; Gene M Dubowchik; John E Macor

doi:10.1016/j.bmcl.2009.04.150

Carbamates as potent calcitonin gene-related peptide antagonists with improved solution stability

Bioorg Med Chem Lett. 2009 Jul 1;19(13):3555-8. doi: 10.1016/j.bmcl.2009.04.150. Epub 2009 May 8.

Authors

Andrew P Degnan¹, Charles M Conway, Richard A Dalterio, Robert Macci, Stephen E Mercer, Richard Schartman, Cen Xu, Gene M Dubowchik, John E Macor

Affiliation

¹ Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA. andrew.degnan@bms.com

PMID: 19467597
DOI: 10.1016/j.bmcl.2009.04.150

Abstract

The calcitonin gene-related peptide (CGRP) receptor has been implicated in the pathogenesis of migraine. A class of urethanamide derivatives has been identified as potent inhibitors of the CGRP receptor. Compound 20 was found to be among the most potent (IC(50)=17pM). It was shown to retain excellent aqueous solubility (>50mg/mL, pH 7) while dramatically improving solution stability as compared to our previously disclosed development candidate, BMS-694153 (1).

MeSH terms

Calcitonin Gene-Related Peptide Receptor Antagonists*
Carbamates / chemical synthesis
Carbamates / chemistry*
Carbamates / pharmacology
Drug Stability
Humans
Indazoles / chemistry*
Migraine Disorders / drug therapy
Quinazolinones / chemistry*
Quinolones / chemical synthesis
Quinolones / chemistry*
Quinolones / pharmacology
Receptors, Calcitonin Gene-Related Peptide / metabolism

Substances

4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide
Calcitonin Gene-Related Peptide Receptor Antagonists
Carbamates
Indazoles
Quinazolinones
Quinolones
Receptors, Calcitonin Gene-Related Peptide