title: Discovery of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): an oral calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine.
abstract: Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.
authors.affiliation: Molecular Sciences and Candidate Optimization, Disease Sciences and Biologics, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States. guanglin.luo@bms.com
authors.forename: Guanglin
authors.initials: G
authors.lastname: Luo
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Charles M
authors.initials: CM
authors.lastname: Conway
authors.forename: Rex
authors.initials: R
authors.lastname: Denton
authors.forename: Deborah
authors.initials: D
authors.lastname: Keavy
authors.forename: Laura
authors.initials: L
authors.lastname: Signor
authors.forename: Walter
authors.initials: W
authors.lastname: Kostich
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Lentz
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Santone
authors.forename: Richard
authors.initials: R
authors.lastname: Schartman
authors.forename: Marc
authors.initials: M
authors.lastname: Browning
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
authors.forename: John G
authors.initials: JG
authors.lastname: Houston
authors.forename: Gene M
authors.initials: GM
authors.lastname: Dubowchik
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D000284:Administration, Oral; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors*; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008881:Migraine Disorders / Q000188:drug therapy*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D010880:Piperidines; D011725:Pyridines; C578443:rimegepant sulfate; D015740:Calcitonin Gene-Related Peptide