2. Academic Validation
  3. Indole cytosolic phospholipase A2 alpha 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

Indole cytosolic phospholipase A2 alpha 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

  • J Med Chem. 2008 Jun 26;51(12):3388-413. doi: 10.1021/jm701467e.
John C McKew 1,  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 Goodwin,  Leo Albert,  Xin Xu,  Frances Donahue,  M Sherry Ku,  James Keith,  Cheryl L Nickerson-Nutter,  William M Abraham,  Cara Williams,  Martin Hegen,  James D Clark
Affiliations

Affiliation

  • 1 Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. jmckew@wyeth.com
PMID: 18498150 DOI: 10.1021/jm701467e
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.

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