408501-48-4Relevant articles and documents
Design and synthesis of a novel and potent series of inhibitors of cytosolic phospholipase A2 based on a 1,3-disubstituted propan-2-one skeleton
Connolly, Stephen,Bennion, Colin,Botterell, Sarah,Croshaw, Pamela J.,Hallam, Catherine,Hardy, Kim,Hartopp, Paul,Jackson, Clive G.,King, Sarah J.,Lawrence, Louise,Mete, Antonio,Murray, David,Robinson, David H.,Smith, Gillian M.,Stein, Linda,Walters, Iain,Wells, Edward,Withnall, W. John
, p. 1348 - 1362 (2007/10/03)
Using knowledge of the substrate specificity of cPLA2 (phospholipases A2), 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 cPLA2 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 cPLA2 described to date being more than 20-fold more active against the isolated enzyme (IC50 = 0.03 μM) than the standard cPLA2 inhibitor, arachidonyl trifluoromethyl ketone (AACOCF3), and also greater than 10-fold more active than AACOCF3 against the cellular production of arachidonic acid by HL60 cells (IC50 = 2.8 μM).
