title: Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: discovery of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1- (2,2,2-trifluoroethyl)azepan-3-yl]-4- (2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin- 1-yl)piperidine-1-carboxamide (MK-0974).
abstract: Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. daniel_paone@merck.com
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Paone
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Shaw
authors.forename: Diem N
authors.initials: DN
authors.lastname: Nguyen
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
authors.forename: James Z
authors.initials: JZ
authors.lastname: Deng
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koblan
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.forename: Victor K
authors.initials: VK
authors.lastname: Johnston
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wong
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Miller-Stein
authors.forename: James C
authors.initials: JC
authors.lastname: Hershey
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002463:Cell Membrane Permeability; D004285:Dogs; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D008881:Migraine Disorders / Q000188:drug therapy*; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; C525458:telcagepant