Structure‐Based Design, Synthesis, and Biological Evaluation of Imidazo[4, 5‐b]pyridin‐2‐one‐Based p38 MAP Kinase Inhibitors: Part 1. (18th April 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; Snell, Gyorgy; Bertsch, Ryan; Nguyen, Jasmine; Sang, Bi‐Ching; Miwatashi, Seiji
• Is Part Of: ChemMedChem. Volume 14:Number 10(2019)
• Page Start: 1022
• Page End: 1030
• Publication Date: 2019-04-18
• Subjects: imidazo[4, 5-b]pyridin-2-ones -- inhibitors -- p38 MAP kinase -- rheumatoid arthritis -- structure-based design; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900129
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: We identified a lead series of p38 mitogen‐activated protein kinase inhibitors using a structure‐based design strategy from high‐throughput screening of hit compound1 . X‐ray crystallography of1 with the kinase showed an infrequent flip of the peptide bond between Met109 and Gly110, which was considered to lead to high kinase selectivity. Our structure‐based design strategy was to conduct scaffold transformation of1 with maintenance of hydrogen bond interactions with the flipped hinge backbone of the enzyme. In accordance with this strategy, we focused on scaffold transformation to identify imidazo[4, 5‐ b ]pyridin‐2‐one derivatives as potent inhibitors of the p38 MAP kinase. Of the compounds evaluated, 21 was found to be a potent inhibitor of the p38 MAP kinase, lipopolysaccharide‐induced tumor necrosis factor‐α (TNF‐α) production in human monocytic leukemia cells, and TNF‐α‐induced production of interleukin‐8 in human whole blood cells. Herein we describe the discovery of potent and orally bioavailable imidazo[4, 5‐ b ]pyridin‐2‐one‐based p38 MAP kinase inhibitors that suppressed cytokine production in a human whole blood cell‐based assay. Abstract : Scaffold hopping : High‐throughput screening identified a carbonylpiperidine derivative as a p38 MAP kinase inhibitor hit compound. Based on X‐ray crystallographic analysis of the complex between this hit and the enzyme, structure‐based design led to potent and orally available imidazo[4, 5‐ b ]pyridin‐2‐one‐based p38 MAP kinase inhibitors.