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) …

…, Y Hu, L Chen, SJ Kirincich, R Michalak…

Index: McKew, John C.; Lee, Katherine L.; Shen, Marina W. H.; Thakker, Paresh; Foley, Megan A.; Behnke, Mark L.; Hu, Baihua; Sum, Fuk-Wah; Tam, Steve; Hu, Yonghan; Chen, Lihren; Kirincich, Steven J.; Michalak, Ronald; Thomason, Jennifer; Ipek, Manus; Wu, Kun; Wooder, Lane; Ramarao, Manjunath K.; Murphy, Elizabeth A.; Goodwin, Debra G.; Albert, Leo; Xu, Xin; Donahue, Frances; Ku, M. Sherry; Keith, James; Nickerson-Nutter, Cheryl L.; Abraham, William M.; Williams, Cara; Hegen, Martin; Clark, James D. Journal of Medicinal Chemistry, 2008 , vol. 51, # 12 p. 3388 - 3413

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Citation Number: 73

Abstract

The optimization of a class of indole cPLA2α 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 cPLA2α in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood ...