Synthesis and biological activity of a series of tetrasubstituted-imidazoles as P2X(7) antagonists

Robert J Gleave; Daryl S Walter; Paul J Beswick; Elena Fonfria; Anton D Michel; Shilina A Roman; Sac-Pham Tang

doi:10.1016/j.bmcl.2010.05.018

Synthesis and biological activity of a series of tetrasubstituted-imidazoles as P2X(7) antagonists

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4951-4. doi: 10.1016/j.bmcl.2010.05.018. Epub 2010 Jun 25.

Authors

Robert J Gleave¹, Daryl S Walter, Paul J Beswick, Elena Fonfria, Anton D Michel, Shilina A Roman, Sac-Pham Tang

Affiliation

¹ Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. [email protected]

PMID: 20634071
DOI: 10.1016/j.bmcl.2010.05.018

Abstract

A series of analogues of the pyrazole lead 1 were synthesized in which the heterocyclic core was replaced with an imidazole. A number of potent antagonists were identified and structure-activity relationships (SAR) were investigated both with respect to activity at the P2X(7) receptor and in vitro metabolic stability. Compound 10 was identified as a potent P2X(7) antagonist with reduced in vitro metabolism and high solubility.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / pharmacology
Purinergic P2 Receptor Antagonists*
Pyrazoles / chemistry
Rats
Receptors, Purinergic P2 / metabolism
Receptors, Purinergic P2X7
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Imidazoles
P2RX7 protein, human
Purinergic P2 Receptor Antagonists
Pyrazoles
Receptors, Purinergic P2
Receptors, Purinergic P2X7
pyrazole