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).
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).
Paone
Daniel V
DV
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. daniel_paone@merck.com
Shaw
Anthony W
AW
Nguyen
Diem N
DN
Burgey
Christopher S
CS
Deng
James Z
JZ
Kane
Stefanie A
SA
Koblan
Kenneth S
KS
Salvatore
Christopher A
CA
Mosser
Scott D
SD
Johnston
Victor K
VK
Wong
Bradley K
BK
Miller-Stein
Cynthia M
CM
Hershey
James C
JC
Graham
Samuel L
SL
Vacca
Joseph P
JP
Williams
Theresa M
TM
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
D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; C525458:telcagepant