Structure-based design and subsequent optimization of 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase

被引：24

作者：

Cogan, D. A. ^{[1
]}

Aungst, R. ^{[4
]}

Breinlinger, E. C. ^{[4
]}

Fadra, T. ^{[1
]}

Goldberg, D. R. ^{[1
]}

Hao, M. H. ^{[1
]}

Kroe, R. ^{[3
]}

Moss, N. ^{[1
]}

Pargellis, C. ^{[2
]}

Qian, K. C. ^{[1
]}

Swinamer, A. D. ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Ctr Res & Dev, Dept Med Chem, Ridgefield, CT 06877 USA

[2] Boehringer Ingelheim Pharmaceut Inc, Ctr Res & Dev, Dept Immunol & Inflammat, Ridgefield, CT 06877 USA

[3] Boehringer Ingelheim Pharmaceut Inc, Ctr Res & Dev, Dept Biol & Biomol Sci, Ridgefield, CT 06877 USA

[4] AMRI, Albany, NY 12203 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 11期

关键词：

p38; kinase; p38a; MAPK; MAP kinase; inhibitors; triazoles; structure-based drug design;

D O I：

10.1016/j.bmcl.2008.04.043

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：3251 / 3255

页数：5

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