The discovery of highly potent CGRP receptor antagonists

Bioorg Med Chem Lett. 2009 Jan 1;19(1):214-7. doi: 10.1016/j.bmcl.2008.10.106. Epub 2008 Oct 31.

Abstract

Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Calcitonin Gene-Related Peptide Receptor Antagonists*
  • Dogs
  • Drug Discovery
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacology
  • Macaca mulatta
  • Oxindoles
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship

Substances

  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Indoles
  • Oxindoles
  • Spiro Compounds
  • 2-oxindole