title: Carbamates as potent calcitonin gene-related peptide antagonists with improved solution stability.
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).
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA. andrew.degnan@bms.com
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Degnan
authors.forename: Charles M
authors.initials: CM
authors.lastname: Conway
authors.forename: Richard A
authors.initials: RA
authors.lastname: Dalterio
authors.forename: Robert
authors.initials: R
authors.lastname: Macci
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Mercer
authors.forename: Richard
authors.initials: R
authors.lastname: Schartman
authors.forename: Cen
authors.initials: C
authors.lastname: Xu
authors.forename: Gene M
authors.initials: GM
authors.lastname: Dubowchik
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D007191:Indazoles / Q000737:chemistry*; D008881:Migraine Disorders / Q000188:drug therapy; D052999:Quinazolinones / Q000737:chemistry*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism
chemical_list: C531228:4-(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; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002219:Carbamates; D007191:Indazoles; D052999:Quinazolinones; D015363:Quinolones; D018015:Receptors, Calcitonin Gene-Related Peptide