Discovery of 2-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-5-(5-fluoropyrimidin-2-yl)benzamide as a potent and CNS penetrable P2X7 receptor antagonist

Xiangyang Chen; Betsy Pierce; Win Naing; Margaret L Grapperhaus; Dennis P Phillion

doi:10.1016/j.bmcl.2010.03.094

Discovery of 2-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-5-(5-fluoropyrimidin-2-yl)benzamide as a potent and CNS penetrable P2X7 receptor antagonist

Bioorg Med Chem Lett. 2010 May 15;20(10):3107-11. doi: 10.1016/j.bmcl.2010.03.094. Epub 2010 Mar 30.

Authors

Xiangyang Chen¹, Betsy Pierce, Win Naing, Margaret L Grapperhaus, Dennis P Phillion

Affiliation

¹ Department of Medicinal Chemistry, Pfizer St. Louis Research Laboratories, Chesterfield, MO 63017, USA. xiangyang.chen@hotmail.com

PMID: 20392639
DOI: 10.1016/j.bmcl.2010.03.094

Abstract

Focused SAR studies were carried out around 5-heteroaryl and 1-amide portions of the 2-chlorobenzamide scaffold, resulting in the discovery of a potent, metabolically stable and centrally penetrable antagonist against P2X(7) receptor.

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / pharmacokinetics
Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / pharmacokinetics
Central Nervous System / drug effects
Drug Discovery
Humans
Male
Microsomes, Liver / metabolism
Purinergic P2 Receptor Antagonists*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Rats
Rats, Sprague-Dawley
Receptors, Purinergic P2 / metabolism
Receptors, Purinergic P2X7
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents
Benzamides
P2RX7 protein, human
Purinergic P2 Receptor Antagonists
Pyrimidines
Receptors, Purinergic P2
Receptors, Purinergic P2X7