Benzenesulfonamide indole inhibitors of cytosolic phospholipase A2α:: Optimization of in vitro potency and rat pharmacokinetics for oral efficacy

被引：27

作者：

Lee, Katherine L. ^{[1
]}

Behnke, Mark L. ^{[1
]}

Foley, Megan A. ^{[1
]}

Chen, Lihren ^{[1
]}

Wang, Weiheng ^{[1
]}

Vargas, Richard ^{[1
]}

Nunez, Jill ^{[1
]}

Tam, Steve ^{[1
]}

Mollova, Nevena ^{[2
]}

Xu, Xin ^{[2
]}

Shen, Marina W. H. ^{[3
]}

Ramarao, Manjunath K. ^{[3
]}

Goodwin, Debra G. ^{[3
]}

Nickerson-Nutter, Cheryl L. ^{[3
]}

Abraham, William M. ^{[4
]}

Williams, Cara ^{[3
]}

Clark, James D. ^{[3
]}

McKew, John C. ^{[1
]}

机构：

[1] Wyeth Ayerst Res, Dept Chem & Screening Sci, Cambridge, MA 02140 USA

[2] Wyeth Ayerst Res, Dept Drug Safety & Metab, Andover, MA 01810 USA

[3] Wyeth Ayerst Res, Dept Inflammat, Cambridge, MA 02140 USA

[4] Mt Sinai Med Ctr, Miami Beach, FL 33140 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 03期

关键词：

phospholipase; inflammation; inhibitor; pharmacokinetics; formulation; animal model; carrageenan paw edema; asthma;

D O I：

10.1016/j.bmc.2007.10.060

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The synthesis and structure-activity relationship of a series of benzenesulfonamide indole inhibitors of cPLA(2)alpha are described. Substitution of the benzenesulfonamide led to analogues with 50-fold improvement in potency versus the unsubstituted benzenesulfonamide lead compound. Rat pharmacokinetics in a minimal formulation was used to prioritize compounds, leading to the discovery of a potent inhibitor of cPLA(2)alpha With oral efficacy in models of rat carrageenan paw edema and Ascaris suum airway challenge in naturally sensitized sheep. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：1345 / 1358

页数：14

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