Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor.

Abstract

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.

• Authors: Muna H Abdi, Paul J Beswick, Andy Billinton, Laura J Chambers, Andrew Charlton, Sue D Collins, Katharine L Collis, David K Dean, Elena Fonfria, Robert J Gleave, Clarisse L Lejeune, David G Livermore, Stephen J Medhurst, Anton D Michel, Andrew P Moses, Lee Page, Sadhana Patel, Shilina A Roman, Stefan Senger, Brian Slingsby, Jon G A Steadman, Alexander J Stevens, Daryl S Walter
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 17 Pg. 5080-4 (Sep 01 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20673717 (Publication Type: Journal Article)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Amides
• Purinergic P2 Receptor Antagonists
• Receptors, Purinergic P2X7
• Pyrrolidonecarboxylic Acid

Topics

• Amides (chemistry, pharmacology)
• Drug Discovery
• Models, Molecular
• Purinergic P2 Receptor Antagonists (chemistry, pharmacology)
• Pyrrolidonecarboxylic Acid (chemistry)
• Receptors, Purinergic P2X7 (drug effects)
• Structure-Activity Relationship