Discovery of Ecopladib, an Indole Inhibitor of Cytosolic Phospholipase A2
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- 作者：Katherine L. Lee ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：March 22, 2007
- 年：2007
- 卷：50
- 期：6
- 页码：1380 - 1400
- 全文大小：408K
- 年卷期：v.50,no.6(March 22, 2007)
- ISSN：1520-4804
文摘
The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipaseA2
(cPLA2, type IVA phospholipase) are described. Inhibitors of cPLA2 are predicted to be efficaciousin treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. Theintroduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of theseinhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a sub-micromolar inhibitor of cPLA2 in the GLU micelle and rat whole blood assays. Compound 123 displayedoral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.
(cPLA2, type IVA phospholipase) are described. Inhibitors of cPLA2 are predicted to be efficaciousin treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. Theintroduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of theseinhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a sub-micromolar inhibitor of cPLA2 in the GLU micelle and rat whole blood assays. Compound 123 displayedoral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.