title: Caprolactams as potent CGRP receptor antagonists for the treatment of migraine.
abstract: 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%).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. anthony_shaw@merck.com
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Shaw
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Paone
authors.forename: Diem N
authors.initials: DN
authors.lastname: Nguyen
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
authors.forename: Ruth Z
authors.initials: RZ
authors.lastname: Rutledge
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koblan
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joeseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
mesh_terms: 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
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; D002209:Caprolactam