title: Inhibition of cytosolic phospholipase A2alpha: hit to lead optimization.
abstract: Compound 1 was previously reported to be a potent inhibitor of cPLA(2)alpha in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC(50) of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzoic acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-gamma-linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA(2)alpha inhibition. The IC(50)s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA(2)alpha and represent well-validated starting points for further optimization.
authors.affiliation: Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA. jmckew@wyeth.com
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.forename: Megan A
authors.initials: MA
authors.lastname: Foley
authors.forename: Paresh
authors.initials: P
authors.lastname: Thakker
authors.forename: Mark L
authors.initials: ML
authors.lastname: Behnke
authors.forename: Frank E
authors.initials: FE
authors.lastname: Lovering
authors.forename: Fuk-Wah
authors.initials: FW
authors.lastname: Sum
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Kun
authors.initials: K
authors.lastname: Wu
authors.forename: Marina W H
authors.initials: MW
authors.lastname: Shen
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Mario
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Shanghao
authors.initials: S
authors.lastname: Liu
authors.forename: Anu
authors.initials: A
authors.lastname: Mahadevan
authors.forename: Howard
authors.initials: H
authors.lastname: Sard
authors.forename: Soo Peang
authors.initials: SP
authors.lastname: Khor
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003600:Cytosol / Q000201:enzymology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054513:Group IV Phospholipases A2; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D010741:Phospholipases A; D054513:Group IV Phospholipases A2