Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 1.
ChemMedChem, 2019/05/17;14(10):1022-1030.
Kaieda A[1], Takahashi M[1], Fukuda H[1], Okamoto R[1], Morimoto S[1], Gotoh M[1], Miyazaki T[1], Hori Y[1], Unno S[1], Kawamoto T[1], Tanaka T[1], Itono S[1], Takagi T[1], Sugimoto H[1], Okada K[1], Snell G[2], Bertsch R[2], Nguyen J[2], Sang BC[2], Miwatashi S[1]
Affiliations
PMID: 30945818DOI: 10.1002/cmdc.201900129
Impact factor: 3.54
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 compound 1. X-ray crystallography of 1 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 of 1 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.
Keywords: imidazo[4,5-b]pyridin-2-ones; inhibitors; p38 MAP kinase; rheumatoid arthritis; structure-based design
MeSH terms
Animals; Antineoplastic Agents; Blood Cells; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Hydrogen Bonding; Imidazoles; Interleukin-8; Lipopolysaccharides; Models, Molecular; Molecular Structure; Protein Binding; Protein Kinase Inhibitors; Pyridines; Pyridones; Rats; Structure-Activity Relationship; Tumor Necrosis Factor-alpha; p38 Mitogen-Activated Protein Kinases
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