| Abstract
| - Using knowledge of the substrate specificity of cPLA2 (phospholipases A2), a novel series ofinhibitors of this enzyme were designed based upon a three point model of inhibitor binding tothe enzyme active site comprising a lipophilic anchor, an electrophilic serine “trap”, and anacidic binding moiety. The resulting 1,3-diheteroatom-substituted propan-2-ones were evaluatedas inhibitors of cPLA2 in both aggregated bilayer and soluble substrate assays. Systematicvariation 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 moietyas a unique serine trap, and a benzoic acid as the acidic binding group. AR-C70484XX wasfound to be among the most potent in vitro inhibitors of cPLA2 described to date being morethan 20-fold more active against the isolated enzyme (IC50 = 0.03 μM) than the standard cPLA2inhibitor, arachidonyl trifluoromethyl ketone (AACOCF3), and also greater than 10-fold moreactive than AACOCF3 against the cellular production of arachidonic acid by HL60 cells (IC50= 2.8 μM).
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