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

George Tora; 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

doi:10.1016/j.bmcl.2013.08.031

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. Epub 2013 Aug 13.

Authors

George Tora¹, 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

Affiliation

¹ Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address: george.tora@bms.com.

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Several new potent CGRP receptor antagonists have been prepared in which the amide bond of lead compound 1 has been replaced by bioisosteric imidazole moieties.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.

MeSH terms

Calcitonin Gene-Related Peptide Receptor Antagonists*
Cell Line, Tumor
Cell Membrane Permeability / drug effects
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / pharmacology
Microsomes / metabolism
Protein Binding
Quinolones / chemical synthesis
Quinolones / chemistry*
Quinolones / pharmacology
Receptors, Calcitonin Gene-Related Peptide / metabolism
Structure-Activity Relationship

Substances

Calcitonin Gene-Related Peptide Receptor Antagonists
Imidazoles
Quinolones
Receptors, Calcitonin Gene-Related Peptide
imidazole