Discovery of ecopladib, an indole inhibitor of cytosolic phospholipase A2α

被引：75
作者：
Lee, Katherine L.
Foley, Megan A.
Chen, Lihren
Behnke, Mark L.
Lovering, Frank E.
Kirincich, Steven J.
Wang, Weiheng
Shim, Jaechul
Tam, Steve
Shen, Marina W. H.
Khor, SooPeang
Xu, Xin
Goodwin, Debra G.
Ramarao, Manjunath K.
Nickerson-Nutter, Cheryl
Donahue, Frances
Ku, M. Sherry
Clark, James D.
McKew, John C.
机构：
[1] Wyeth Ayerst Res, Dept Chem & Screening Sci, Cambridge, MA 02140 USA
[2] Wyeth Ayerst Res, Dept Inflammat, Cambridge, MA 02140 USA
[3] Wyeth Ayerst Res, Dept Drug Safety & Metab, Cambridge, MA 02140 USA
[4] Wyeth Ayerst Res, Dept Chem & Pharmaceut Dev, Cambridge, MA 02140 USA
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 06期
关键词：
D O I：
10.1021/jm061131z
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A(2)alpha (cPLA(2)alpha, type IVA phospholipase) are described. Inhibitors of cPLA(2)alpha 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 cPLA(2)alpha 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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页码：1380 / 1400
页数：21
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