title: Design and synthesis of a novel and potent series of inhibitors of cytosolic phospholipase A(2) based on a 1,3-disubstituted propan-2-one skeleton.
abstract: Using knowledge of the substrate specificity of cPLA(2) (phospholipases A(2)), a novel series of inhibitors of this enzyme were designed based upon a three point model of inhibitor binding to the enzyme active site comprising a lipophilic anchor, an electrophilic serine "trap", and an acidic binding moiety. The resulting 1,3-diheteroatom-substituted propan-2-ones were evaluated as inhibitors of cPLA(2) in both aggregated bilayer and soluble substrate assays. Systematic variation of the lipophilic, electrophilic, and acidic groups revealed a well-defined structure-activity relationship against the enzyme. Optimization of each group led to compound 22 (AR-C70484XX), which contains a decyloxy lipophilic side chain, a 1,3-diaryloxypropan-2-one moiety as a unique serine trap, and a benzoic acid as the acidic binding group. AR-C70484XX was found to be among the most potent in vitro inhibitors of cPLA(2) described to date being more than 20-fold more active against the isolated enzyme (IC(50) = 0.03 microM) than the standard cPLA(2) inhibitor, arachidonyl trifluoromethyl ketone (AACOCF(3)), and also greater than 10-fold more active than AACOCF(3) against the cellular production of arachidonic acid by HL60 cells (IC(50) = 2.8 microM).
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, United Kingdom. steve.connolly@astrazeneca.com
authors.forename: Stephen
authors.initials: S
authors.lastname: Connolly
authors.forename: Colin
authors.initials: C
authors.lastname: Bennion
authors.forename: Sarah
authors.initials: S
authors.lastname: Botterell
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Croshaw
authors.forename: Catherine
authors.initials: C
authors.lastname: Hallam
authors.forename: Kim
authors.initials: K
authors.lastname: Hardy
authors.forename: Paul
authors.initials: P
authors.lastname: Hartopp
authors.forename: Clive G
authors.initials: CG
authors.lastname: Jackson
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: King
authors.forename: Louise
authors.initials: L
authors.lastname: Lawrence
authors.forename: Antonio
authors.initials: A
authors.lastname: Mete
authors.forename: David
authors.initials: D
authors.lastname: Murray
authors.forename: David H
authors.initials: DH
authors.lastname: Robinson
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Smith
authors.forename: Linda
authors.initials: L
authors.lastname: Stein
authors.forename: Iain
authors.initials: I
authors.lastname: Walters
authors.forename: Edward
authors.initials: E
authors.lastname: Wells
authors.forename: W John
authors.initials: WJ
authors.lastname: Withnall
mesh_terms: D016718:Arachidonic Acid / Q000032:analysis / Q000096:biosynthesis; D003600:Cytosol / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology; D008051:Lipid Bilayers / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D011407:Propane / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007659:Ketones; D008051:Lipid Bilayers; D016718:Arachidonic Acid; D010741:Phospholipases A; D011407:Propane