Benzodiazepine calcitonin gene-related peptide (CGRP) receptor antagonists: optimization of the 4-substituted piperidine.
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.
Burgey
Christopher S
CS
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. christopher_burgey@merck.com
Stump
Craig A
CA
Nguyen
Diem N
DN
Deng
James Z
JZ
Quigley
Amy G
AG
Norton
Beth R
BR
Bell
Ian M
IM
Mosser
Scott D
SD
Salvatore
Christopher A
CA
Rutledge
Ruth Z
RZ
Kane
Stefanie A
SA
Koblan
Kenneth S
KS
Vacca
Joseph P
JP
Graham
Samuel L
SL
Williams
Theresa M
TM
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
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010880:Piperidines; D001569:Benzodiazepines; C032727:piperidine; D000242:Cyclic AMP