Structure‐Based Design, Synthesis, and Biological Evaluation of ImidazoPyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 2

• Published in: ChemMedChem 2019-12, Vol.14 (24), p.2093-2101
• Main Authors: 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, Weston, Lane, Bi‐Ching Sang, Kumar Saikatendu, Matsunaga, Shinichiro, Miwatashi, Seiji
• Format: Article
• Language: English
• Subjects: Arthritis; Benzamide; Bioavailability; Collagen; Inhibitors; Kinases; Lead compounds; MAP kinase; Tumor necrosis factor; Tumor necrosis factor-TNF
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900373

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.