Benzodiazepine calcitonin gene-related peptide (CGRP) receptor antagonists: optimization of the 4-substituted piperidine

Bioorg Med Chem Lett. 2006 Oct 1;16(19):5052-6. doi: 10.1016/j.bmcl.2006.07.044. Epub 2006 Aug 2.

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.

MeSH terms

  • Benzodiazepines / chemical synthesis
  • Benzodiazepines / pharmacology*
  • Calcitonin Gene-Related Peptide Receptor Antagonists*
  • Cyclic AMP / antagonists & inhibitors
  • Drug Stability
  • Humans
  • Migraine Disorders / drug therapy*
  • Piperidines / chemical synthesis
  • Piperidines / pharmacology*
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Piperidines
  • Benzodiazepines
  • piperidine
  • Cyclic AMP