Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]Pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 2

被引：4

作者：

Kaieda, Akira ^{[1
]}

Takahashi, Masashi ^{[1
]}

Fukuda, Hiromi ^{[1
]}

Okamoto, Rei ^{[1
]}

Morimoto, Shinji ^{[1
]}

Gotoh, Masayuki ^{[1
]}

Miyazaki, Takahiro ^{[1
]}

Hori, Yuri ^{[1
]}

Unno, Satoko ^{[1
]}

Kawamoto, Tomohiro ^{[1
]}

Tanaka, Toshimasa ^{[1
]}

Itono, Sachiko ^{[1
]}

Takagi, Terufumi ^{[1
]}

Sugimoto, Hiroshi ^{[1
]}

Okada, Kengo ^{[1
]}

Lane, Weston ^{[2
]}

Sang, Bi-Ching ^{[2
]}

Saikatendu, Kumar ^{[2
]}

Matsunaga, Shinichiro ^{[1
]}

Miwatashi, Seiji ^{[1
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan

[2] Takeda Calif, 10410 Sci Ctr Dr, San Diego, CA 92121 USA

来源：

CHEMMEDCHEM | 2019年 / 14卷 / 24期

基金：

美国国家卫生研究院;

关键词：

p38 mitogen-activated protein kinase inhibitors; rheumatoid arthritis; structure-based design; imidazo[4; 5-b]pyridin-2-one derivatives; ACTIVATED PROTEIN-KINASE; RHEUMATOID-ARTHRITIS; ANTIRHEUMATIC DRUGS; DOUBLE-BLIND; ALPHA; DISCOVERY; POTENT; EXPRESSION; ANTIBODY; PATHWAY;

D O I：

10.1002/cmdc.201900373

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We identified novel potent inhibitors of p38 mitogen-activated protein (MAP) kinase using a structure-based design strategy, beginning with lead compound, 3-(butan-2-yl)-6-(2,4-difluoroanilino)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1). To enhance the inhibitory activity of 1 against production of tumor necrosis factor-alpha (TNF-alpha) in human whole blood (hWB) cell assays, we designed and synthesized hybrid compounds in which the imidazo[4,5-b]pyridin-2-one core was successfully linked with the p-methylbenzamide fragment. Among the compounds evaluated, 3-(3-tert-butyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-4-methyl-N-(1-methyl-1H-pyrazol-3-yl)benzamide (25) exhibited potent p38 inhibition, superior suppression of TNF-alpha production in hWB cells, and also significant in vivo efficacy in a rat model of collagen-induced arthritis (CIA). In this paper, we report the discovery of potent, selective, and orally bioavailable imidazo[4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors.

引用

页码：2093 / 2101

页数：9

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