Caprolactams as potent CGRP receptor antagonists for the treatment of migraine.
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Replacements for the benzodiazepine core of an earlier lead structure 1 including 5-, 6-, and 7-membered lactams were explored. Within the 7-membered ring scaffold, phenyl substitution at various positions afforded the potent (3R)-amino-(6S)-phenyl caprolactam template. The phenylimidazolinone privileged structure gave additional potency enhancements, as 24 showed good potency in both CGRP binding (K(i)=2 nM) and cAMP (IC(50)=4 nM) assays and was orally bioavailable in rats (27%).
Shaw
Anthony W
AW
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. anthony_shaw@merck.com
Paone
Daniel V
DV
Nguyen
Diem N
DN
Stump
Craig A
CA
Burgey
Christopher S
CS
Mosser
Scott D
SD
Salvatore
Christopher A
CA
Rutledge
Ruth Z
RZ
Kane
Stefanie A
SA
Koblan
Kenneth S
KS
Graham
Samuel L
SL
Vacca
Joeseph P
JP
Williams
Theresa M
TM
D000284:Administration, Oral; D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002209:Caprolactam / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008881:Migraine Disorders / Q000188:drug therapy*; D008956:Models, Chemical; D051381:Rats
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; D002209:Caprolactam