title: Benzhydrylquinazolinediones: novel cytosolic phospholipase A2alpha inhibitors with improved physicochemical properties.
abstract: 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.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, MA 02140, USA. skirincich@wyeth.com
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kirincich
authors.forename: Jason
authors.initials: J
authors.lastname: Xiang
authors.forename: Neal
authors.initials: N
authors.lastname: Green
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Yang
authors.forename: Jaechul
authors.initials: J
authors.lastname: Shim
authors.forename: Marina W H
authors.initials: MW
authors.lastname: Shen
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
mesh_terms: 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
chemical_list: D001559:Benzhydryl Compounds; D052999:Quinazolinones; D016718:Arachidonic Acid; D054513:Group IV Phospholipases A2