Caprolactams as potent CGRP receptor antagonists for the treatment of migraine

Bioorg Med Chem Lett. 2007 Sep 1;17(17):4795-8. doi: 10.1016/j.bmcl.2007.06.062. Epub 2007 Jun 26.

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%).

MeSH terms

  • Administration, Oral
  • Animals
  • Calcitonin Gene-Related Peptide Receptor Antagonists*
  • Caprolactam / chemical synthesis
  • Caprolactam / chemistry
  • Caprolactam / pharmacology*
  • Chemistry, Pharmaceutical / methods
  • Drug Design
  • Humans
  • Imidazoles / pharmacology
  • Inhibitory Concentration 50
  • Kinetics
  • Migraine Disorders / drug therapy*
  • Models, Chemical
  • Rats

Substances

  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Imidazoles
  • Caprolactam