Inhibition of Cytosolic Phospholipase A₂α: 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.

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…[198] It is notable that the presence of multiple acidic hydrogens in the aryl halide substrate did not interfere with the coupling which had previously been successfully applied in the transformation of simpler members of the series. [199] Augustyns at the University of Antwerp utilized the coupling of a primary amine and bromobenzene during the course of work on the synthesis of selective dipeptidyl peptidase II inhibitors which have potential for the treatment of a range of diseases (Scheme 42). [200] For the synthesis of radiolabelled compounds the reaction time for a cross-coupling is an important factor when dealing with compounds labelled with isotopes with a short half-life.…”

ASB14780, an Orally Active Inhibitor of Group IVA Phospholipase A2, Is a Pharmacotherapeutic Candidate for Nonalcoholic Fatty Liver Disease

“…These findings led us to hypothesize that IVA-PLA 2 inhibitors may be promising candidates for the treatment of NAFLD and NASH. IVA-PLA 2 -specific inhibitors have already been developed by Wyeth Pharmaceuticals, Shionogi Pharmaceuticals, Astra Zeneca, and the Kokotos and Dennis groups, and include indole derivatives (McKew et al, 2003(McKew et al, , 2006(McKew et al, , 2008Lee et al, 2007), pyrrolidinebased compounds (Seno et al, 2000(Seno et al, , 2001Ono et al, 2002;Flamand et al, 2006), propan-2-ones (Connolly et al, 2002;Ludwig et al, 2006;Hess et al, 2007;Fritsche et al, 2008), and 2-oxoamide compounds (Kokotos et al, 2002(Kokotos et al, , 2004Stephens et al, 2006;Six et al, 2007), respectively. Since none of these inhibitors is orally active, the prospect of using an IVA-PLA 2 inhibitor has been limited.…”

Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A2αand fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps

“…Â 4 mm). Autosampler temperature was 10 C, column oven temperature was set to 30 C. The mobile phase consisted of acetonitrile/10 mM ammonium acetate 20:80 (v/v), adjusted to pH 5 with formic acid (A) and acetonitrile/10 mM ammonium acetate 80:20 (v/v), adjusted to pH 5 with formic acid. The following gradient was applied (A%): 0 min: 90; 1 min: 90; 9 min: 0; 11 min: 0; 11.5 min: 90; and 16 min: 90.…”

“…The tosylate moiety of (2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate 23 (30) was substituted with a 4-phenoxyphenoxy residue to give 31. Cleavage of the cyclic acetal structure of 31 was accomplished with aqueous HCl in methanol.…”