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

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.

• Authors: Guanglin Luo, Ling Chen, Rita Civiello, Sokhom S Pin, Cen Xu, Walter Kostich, Michelle Kelley, Charles M Conway, John E Macor, Gene M Dubowchik
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 8 Pg. 2917-21 (Apr 15 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22429470 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Amides
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Pyridines

Topics

• Amides (chemistry, 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, chemistry, pharmacology)