β-aryl-suceinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme

被引:45
作者
Kottirsch, G [1 ]
Koch, G [1 ]
Feifel, R [1 ]
Neumann, U [1 ]
机构
[1] Preclin Res Novartis Pharma AG, CH-4002 Basel, Switzerland
关键词
D O I
10.1021/jm0110993
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFa levels with an ED50 of 1 mg/kg.
引用
收藏
页码:2289 / 2293
页数:5
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