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.

The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.

FUK-WAH SUM and LARRY WEILER. Can. J. Chem. 57,1431 (1979). The anions from P-keto esters or P-diketones were reacted with diethyl phosphorochloridate to yield the corresponding en01 phosphates. These en01 phosphates were coupled with dialkylcuprates to produce the P-substituted a,P-unsaturated esters or ketones in good yield. Starting from acyclic P-keto esters this sequence was used to stereoselectively generate tri-and tetrasubstituted olefins.FUK-WAH SUM et LARRY WEILER. Can. J. Chem. 57,1431 (1979). On a fait rkagir les anions de P-cktoesters ou de P-dicktones avec le phosphorochloridate de dikthyle et Yon a obtenu les phosphates knoliques correspondants. On a effectuk une rkaction de copulation de ces phosphates knoliques avec des cuprates de dialkyles pour conduire, avec de bons rendements, aux cktones ou aux esters a#-non saturks substituks en P. En appliquant cette skrie de rkactions t~ des esters P-cktoniques acycliques, on a obtenu stkrkosklectivement des olefines tri-et tktrasubstituks.[Traduit par le journal]In the past decade there has been wide interest in developing new methods to synthesize tri-and tetrasubstituted alkenes in a stereoselective fashion (1). These alkenes have been very useful in the synthesis of a range of natural products, including insect pheromones and terpenes. Recently, we have been investigating methods to utilize P-keto esters in the synthesis of these types of natural products. Dianions of P-keto esters can be trapped by a variety of electrophiles at the y-carbon (2). These methods have been useful in the synthesis of acetogenins in which the P-keto ester moiety is directly incorporated into the final product (for some examples see ref.3). On the other hand, conversion of the ketone of a P-keto ester into a methylated olefin as shown in [I] would then constitute a method to incorporate an isoprene unit in a synthetic scheme. The utility of this transformation would be further enhanced if any alkyl group could be used in place of the methyl group in [I].Casey and co-workers (4) have reported that acyclic P-keto esters can be stereoselectively converted into either the (E) or (2) en01 acetates which then undergo a stereospecific reaction with lithium dimethylcuprate. These reactions were applied in a synthesis of geraniol (4a) and (52)-7-methyl-3-propyl-2,6-decadien-1-01 (5). This sequence involves treating acyclic P-keto esters with isopropenyl acetate and p-toluenesulfonic acid at high temperature to obtain the (2) en01 acetates (4, 5). Unfortunately these strong acid conditions severely limit the functionality which may be incorporated in R of [I]; indeed this sequence has only been successful when R is a hydrocarbon. Recently, we have prepared the en01 acetates of several cyclic P-keto esters and we find that they do not couple with dialkylcuprates. At low temperatures en01 acetate is recovered, and at higher temperature or after prolonged reaction times the acetate is cleaved to yield a mixture of cyclic P-keto ester and en01 acetate. House and co-workers (6) have sho...

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