Structure-Based Design,Synthesis, and Biological Evaluation of Imidazo[4,5-b]Pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part?2 |
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| Authors: | Akira Kaieda Dr Masashi Takahashi Hiromi Fukuda Dr Rei Okamoto Dr Shinji Morimoto Masayuki Gotoh Takahiro Miyazaki Yuri Hori Satoko Unno Dr Tomohiro Kawamoto Dr Toshimasa Tanaka Dr Sachiko Itono Terufumi Takagi Dr Hiroshi Sugimoto Dr Kengo Okada Dr Weston Lane Dr Bi-Ching Sang Dr Kumar Saikatendu Dr Shinichiro Matsunaga Dr Seiji Miwatashi |
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| Affiliation: | 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa, 251-8555 Japan;2. Takeda California, 10410 Science Center Drive, San Diego, CA 92121 USA |
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| Abstract: | 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-imidazo4,5-b]pyridin-2-one ( 1 ). To enhance the inhibitory activity of 1 against production of tumor necrosis factor-α (TNF-α) in human whole blood (hWB) cell assays, we designed and synthesized hybrid compounds in which the imidazo4,5-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-imidazo4,5-b]pyridin-6-yl)-4-methyl-N-(1-methyl-1H-pyrazol-3-yl)benzamide ( 25 ) exhibited potent p38 inhibition, superior suppression of TNF-α 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 imidazo4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors. |
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| Keywords: | p38 mitogen-activated protein kinase inhibitors rheumatoid arthritis structure-based design imidazo[4 5-b]pyridin-2-one derivatives |
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