Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: discovery of MK-2918.
In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918).
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. daniel_paone@merck.com
Daniel V
DV
Paone
Diem N
DN
Nguyen
Anthony W
AW
Shaw
Christopher S
CS
Burgey
Craig M
CM
Potteiger
James Z
JZ
Deng
Scott D
SD
Mosser
Christopher A
CA
Salvatore
Sean
S
Yu
Shane
S
Roller
Stefanie A
SA
Kane
Harold G
HG
Selnick
Joseph P
JP
Vacca
Theresa M
TM
Williams
D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002209:Caprolactam / Q000737:chemistry; D002478:Cells, Cultured; D004285:Dogs; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008253:Macaca mulatta; D008881:Migraine Disorders / Q000188:drug therapy; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
D018712:Analgesics, Non-Narcotic; D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; C560208:MK 2918; D002209:Caprolactam