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.
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.
Chen
Xiangyang
X
Department of Medicinal Chemistry, Pfizer St. Louis Research Laboratories, Chesterfield, MO 63017, USA. xiangyang.chen@hotmail.com
Pierce
Betsy
B
Naing
Win
W
Grapperhaus
Margaret L
ML
Phillion
Dennis P
DP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002490:Central Nervous System / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D058919:Purinergic P2 Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D001549:Benzamides; C546468:P2RX7 protein, human; D058919:Purinergic P2 Receptor Antagonists; D011743:Pyrimidines; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7