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

• Published in: Journal of medicinal chemistry Vol. 51; no. 12; pp. 3388 - 3413
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.06.2008
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arthritis, Experimental - drug therapy; Benzoates - chemical synthesis; Benzoates - chemistry; Benzoates - pharmacology; Biological Availability; Bronchoconstriction - drug effects; Calorimetry; Carrageenan; Cell Line; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Edema - chemically induced; Edema - drug therapy; Group IV Phospholipases A2 - antagonists & inhibitors; Humans; In Vitro Techniques; Isoenzymes - antagonists & inhibitors; Male; Mice; Protein Binding; Rats; Rats, Sprague-Dawley; Sheep; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701467e

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 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.