Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4, 5‐b]Pyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 2. (7th November 2019)

• Record Type: Journal Article
• 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; Lane, Weston; Sang, Bi‐Ching; Saikatendu, Kumar; Matsunaga, Shinichiro; Miwatashi, Seiji
• Is Part Of: ChemMedChem. Volume 14:Number 24(2019)
• Page Start: 2093
• Page End: 2101
• Publication Date: 2019-11-07
• Subjects: p38 mitogen-activated protein kinase inhibitors -- rheumatoid arthritis -- structure-based design -- imidazo[4, 5-b]pyridin-2-one derivatives; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900373
• Languages: English
• ISSNs: 1860-7179

Abstract

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‐2 H ‐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‐1 H ‐imidazo[4, 5‐ b ]pyridin‐6‐yl)‐4‐methyl‐ N ‐(1‐methyl‐1 H ‐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. Abstract : Scaffold hopping : Structure‐based design with X‐ray crystallographic analysis of the complex between lead compound 1 and p38 MAP kinase, and expanding an approach for direct hydrogen bond formation with the back pocket residues of the kinase, led to potent p38 MAP kinase inhibitor 25, which was found to exhibit strong suppression of TNF‐α production in human whole blood and to have excellent in vivo efficacy in a rat CIA model.