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

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

doi:10.1016/j.bmcl.2010.07.033

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

Bioorg Med Chem Lett. 2010 Sep 1;20(17):5080-4. doi: 10.1016/j.bmcl.2010.07.033. Epub 2010 Jul 14.

Affiliation

¹ Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

PMID: 20673717
DOI: 10.1016/j.bmcl.2010.07.033

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.

MeSH terms

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

Substances

Amides
Purinergic P2 Receptor Antagonists
Receptors, Purinergic P2X7
Pyrrolidonecarboxylic Acid