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: Christopher S Burgey, Craig A Stump, Diem N Nguyen, James Z Deng, Amy G Quigley, Beth R Norton, Ian M Bell, Scott D Mosser, Christopher A Salvatore, Ruth Z Rutledge, Stefanie A Kane, Kenneth S Koblan, Joseph P Vacca, Samuel L Graham, Theresa M Williams
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 16 Issue 19 Pg. 5052-6 (Oct 01 2006) ISSN: 0960-894X [Print] England
• PMID: 16889959 (Publication Type: Journal Article)

Chemical References

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

Topics

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