Benzhydrylquinazolinediones: novel cytosolic phospholipase A2alpha inhibitors with improved physicochemical properties.
The synthesis and optimization of a class of trisubstituted quinazoline-2,4(1H,3H)-dione cPLA(2)alpha inhibitors are described. Utilizing pharmacophores that were found to be important in our indole series, we discovered inhibitors with reduced lipophilicity and improved aqueous solubility. These compounds are active in whole blood assays, and cell-based assay results indicate that prevention of arachidonic acid release arises from selective cPLA(2)alpha inhibition.
Kirincich
Steven J
SJ
Chemical and Screening Sciences, Wyeth Research, MA 02140, USA. skirincich@wyeth.com
Xiang
Jason
J
Green
Neal
N
Tam
Steve
S
Yang
Hui Y
HY
Shim
Jaechul
J
Shen
Marina W H
MW
Clark
James D
JD
McKew
John C
JC
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
D001559:Benzhydryl Compounds; D052999:Quinazolinones; D016718:Arachidonic Acid; D054513:Group IV Phospholipases A2