Calcitonin gene-related peptide (CGRP) receptor antagonists: pyridine as a replacement for a core amide group

Guanglin Luo; Ling Chen; Rita Civiello; Sokhom S Pin; Cen Xu; Walter Kostich; Michelle Kelley; Charles M Conway; John E Macor; Gene M Dubowchik

doi:10.1016/j.bmcl.2012.02.065

Calcitonin gene-related peptide (CGRP) receptor antagonists: pyridine as a replacement for a core amide group

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2917-21. doi: 10.1016/j.bmcl.2012.02.065. Epub 2012 Mar 3.

Authors

Guanglin Luo¹, Ling Chen, Rita Civiello, Sokhom S Pin, Cen Xu, Walter Kostich, Michelle Kelley, Charles M Conway, John E Macor, Gene M Dubowchik

Affiliation

¹ Molecular Sciences and Candidate Optimization, Neuroscience Biology, Bristol-Myers Squibb Research & Development, Wallingford, CT 06492, USA. guanglin.luo@bms.com

PMID: 22429470
DOI: 10.1016/j.bmcl.2012.02.065

Abstract

In our continuing efforts to identify CGRP receptor antagonists that can be dosed orally for the treatment of migraine headache, we have investigated a pyridine bioisosteric replacement of a polar amide portion of a previous lead compound, BMS-694153. Pyridine derivatives were discovered and their SAR was studied. Some of them showed excellent binding potency. However, oral bioavailability was low, even for compounds with good Caco-2 cell permeability.

MeSH terms

Amides / chemistry
Amides / pharmacology
Caco-2 Cells
Calcitonin Gene-Related Peptide Receptor Antagonists*
Humans
Inhibitory Concentration 50
Migraine Disorders / drug therapy
Molecular Structure
Protein Binding / drug effects
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology

Substances

Amides
Calcitonin Gene-Related Peptide Receptor Antagonists
Pyridines