Indole Cytosolic Phospholipase A₂ α Inhibitors: Discovery and in Vitro and in Vivo Characterization of 4-{3-[5-Chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid, Efipladib

Abstract

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.

Neutrophil-Derived Cytosolic PLA2α Contributes to Bacterial-Induced Neutrophil Transepithelial Migration

“…Additionally, cPLA2α has been suggested to play a role in pulmonary fibrosis, as cPLA2α deficient mice are protected from the inflammatory response and fibrosis brought on by bleomycin exposure(33). Pre-clinical studies have assessed the effect of a cPLA2α inhibitor, PF-5212372, on animal models of allergic asthma, but have not considered neutrophilic responses(54, 55). Therefore, cPLA2α has been shown to play a role in the pulmonary disease, but a precise mechanism of action has not been described.…”

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.…”

Cytosolic phospholipase A2 and its role in cancer

“…However, these inhibitors have low specificity. Recently, other inhibitors with high specificity have been found-namely, indole-derivative inhibitors [14] and 2-oxoamide inhibitors [15] . These 2 types of inhibitor have been tested in both cells and animal models, and have been shown to have fewer side effects than the classic inhibitors and therefore might potentially be used in developing drugs for treating disease in which cPLA 2 a is dysfunctional.…”