2. Academic Validation
  3. Discovery of Ecopladib, an indole inhibitor of cytosolic phospholipase A2alpha

Discovery of Ecopladib, an indole inhibitor of cytosolic phospholipase A2alpha

  • J Med Chem. 2007 Mar 22;50(6):1380-400. doi: 10.1021/jm061131z.
Katherine L Lee 1,  Megan A Foley,  Lihren Chen,  Mark L Behnke,  Frank E Lovering,  Steven J Kirincich,  Weiheng Wang,  Jaechul Shim,  Steve Tam,  Marina W H Shen,  Soopeang Khor,  Xin Xu,  Debra G Goodwin,  Manjunath K Ramarao,  Cheryl Nickerson-Nutter,  Frances Donahue,  M Sherry Ku,  James D Clark,  John C McKew
Affiliations

Affiliation

  • 1 Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA. klee@wyeth.com
PMID: 17305324 DOI: 10.1021/jm061131z
Abstract

The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic Phospholipase A2alpha (cPLA2alpha, type IVA Phospholipase) are described. Inhibitors of cPLA2alpha are predicted to be efficacious in treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. The introduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of these inhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a sub-micromolar inhibitor of cPLA2alpha in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.

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