Substituted isoxazoles as potent inhibitors of p38 MAP kinase

被引：31

作者：

Laufer, Stefan A.

Margutti, Simona

Fritz, Martina D.

机构：

[1] Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University of Tübingen, 72076 Tübingen

来源：

CHEMMEDCHEM | 2006年 / 1卷 / 02期

关键词：

Cytochromes; Enzymes; Inhibitors; Isoxazoles; p38 MAP kinase;

D O I：

10.1002/cmdc.200500025

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In a continuous effort to develop improved p38 MAP (mitogen-activated protein) kinase inhibitors, we focused our attention on the suitability of the isoxozole ring as a bioisosteric replacement for the imidazole ring of SB-203580. 3,4- and 4,5-disubstituted as well as 3,4,5-trisubstituted isoxazole derivatives were synthesized. These compounds were tested in an in vitro enzyme-linked immunosorbent assay of isolated p38 MAP kinase and for inhibitory potency against cytochrome P450. Compound 4a displays a highly promising profile for development as an anti-inflammatory agent owing to its enhanced suppression of cytokine release, decreased affinity for cytochrome P450 and a twofold decrease in IC50 toward isolated p38 MAP kinase.

引用

页码：197 / 207

页数：11

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