1268346-95-7Relevant academic research and scientific papers
Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]Pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 2
Kaieda, Akira,Takahashi, Masashi,Fukuda, Hiromi,Okamoto, Rei,Morimoto, Shinji,Gotoh, Masayuki,Miyazaki, Takahiro,Hori, Yuri,Unno, Satoko,Kawamoto, Tomohiro,Tanaka, Toshimasa,Itono, Sachiko,Takagi, Terufumi,Sugimoto, Hiroshi,Okada, Kengo,Lane, Weston,Sang, Bi-Ching,Saikatendu, Kumar,Matsunaga, Shinichiro,Miwatashi, Seiji
, p. 2093 - 2101 (2019)
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-α (TNF-α) 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-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 imidazo[4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors.
