Preparation of imidazoles as potent calcitonin gene-related peptide (CGRP) antagonists

  • Bioorg Med Chem Lett. 2013 Oct 15;23(20):5684-8. doi: 10.1016/j.bmcl.2013.08.031.
George Tora  1 ,  Andrew P Degnan ,  Charles M Conway ,  Walter A Kostich ,  Carl D Davis ,  Sokhom S Pin ,  Richard Schartman ,  Cen Xu ,  Kimberly A Widmann ,  John E Macor ,  Gene M Dubowchik
Affiliations
  • 1. Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address: [email protected].
PMID: 23993336 DOI: 10.1016/j.bmcl.2013.08.031
Abstract

Several new potent CGRP Receptor antagonists have been prepared in which the amide bond of lead compound 1 has been replaced by bioisosteric imidazole moieties. Substitution at N-1 of the imidazole was optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of the imidazole to form tetrahydroimidazo[1,5-a]pyrazine 43 gave substantially improved permeability.

Keywords
CGRP; CGRP receptor antagonists; Imidazoles; Migraine; Migraineurs.