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.
Muna H Abdi  1 ,  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
Affiliations
  • 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.

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