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

John C. McKew, Katherine L. Lee, Marina W.H. Shen, Paresh Thakker, Megan A. Foley, Mark L. Behnke, Baihua Hu, Fuk Wah Sum, Steve Tam, Yonghan Hu, Lihren Chen, Steven J. Kirincich, Ronald Michalak, Jennifer Thomason, Manus Ipek, Kun Wu, Lane Wooder, Manjunath K. Ramarao, Elizabeth A. Murphy, Debra G. GoodwinLeo Albert, Xin Xu, Frances Donahue, M. Sherry Ku, James Keith, Cheryl L. Nickerson-Nutter, William M. Abraham, Cara Williams, Martin Hegen, James D. Clark

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)3388-3413
Number of pages26
JournalJournal of Medicinal Chemistry
Volume51
Issue number12
DOIs
StatePublished - Jun 26 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Indole cytosolic phospholipase A<sub>2</sub> 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'. Together they form a unique fingerprint.

Cite this