title: Benzodiazepine calcitonin gene-related peptide (CGRP) receptor antagonists: optimization of the 4-substituted piperidine.
abstract: In our continuing effort to identify CGRP receptor antagonists for the acute treatment of migraine, we have undertaken a study to evaluate alternative 4-substituted piperidines to the lead dihydroquinazolinone 1. In this regard, we have identified the piperidinyl-azabenzimidazolone and phenylimidazolinone structures which, when incorporated into the benzodiazepine core, afford potent CGRP receptor antagonists (e.g., 18 and 29). These studies produced a potent analog (18) which overcomes the instability issues associated with the lead structure 1. A general pharmacophore for the 4-substituted piperidine component of these CGRP receptor antagonists is also presented.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. christopher_burgey@merck.com
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.forename: Diem N
authors.initials: DN
authors.lastname: Nguyen
authors.forename: James Z
authors.initials: JZ
authors.lastname: Deng
authors.forename: Amy G
authors.initials: AG
authors.lastname: Quigley
authors.forename: Beth R
authors.initials: BR
authors.lastname: Norton
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
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: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D004355:Drug Stability; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy*; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010880:Piperidines; D001569:Benzodiazepines; C032727:piperidine; D000242:Cyclic AMP