Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide antagonists of the P2X(7) receptor

Lee Abberley; Aude Bebius; Paul J Beswick; Andy Billinton; Katharine L Collis; David K Dean; Elena Fonfria; Robert J Gleave; Stephen J Medhurst; Anton D Michel; Andrew P Moses; Sadhana Patel; Shilina A Roman; Tiziana Scoccitti; Beverley Smith; Jon G A Steadman; Daryl S Walter

doi:10.1016/j.bmcl.2010.09.101

Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide antagonists of the P2X(7) receptor

Bioorg Med Chem Lett. 2010 Nov 15;20(22):6370-4. doi: 10.1016/j.bmcl.2010.09.101. Epub 2010 Sep 22.

Authors

Lee Abberley¹, Aude Bebius, Paul J Beswick, Andy Billinton, Katharine L Collis, David K Dean, Elena Fonfria, Robert J Gleave, Stephen J Medhurst, Anton D Michel, Andrew P Moses, Sadhana Patel, Shilina A Roman, Tiziana Scoccitti, Beverley Smith, Jon G A Steadman, Daryl S Walter

Affiliation

¹ Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.

PMID: 20934331
DOI: 10.1016/j.bmcl.2010.09.101

Abstract

A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.

MeSH terms

Administration, Oral
Animals
Biological Availability
Half-Life
Haplorhini
Imidazolines / administration & dosage
Imidazolines / chemistry
Imidazolines / pharmacokinetics
Imidazolines / pharmacology*
Purinergic Antagonists / administration & dosage
Purinergic Antagonists / chemistry
Purinergic Antagonists / pharmacokinetics
Purinergic Antagonists / pharmacology*
Rats
Receptors, Purinergic P2X7 / drug effects*

Substances

Imidazolines
Purinergic Antagonists
Receptors, Purinergic P2X7