Loading
PDBj
MenuPDBj@FacebookPDBj@X(formerly Twitter)PDBj@BlueSkyPDBj@YouTubewwPDB FoundationwwPDB
RCSB PDBPDBeBMRBAdv. SearchSearch help

6M95

Structure-based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridine-2-one based p38 MAP Kinase Inhibitors by scaffold hopping: compound 1

Summary for 6M95
Entry DOI10.2210/pdb6m95/pdb
DescriptorMitogen-activated protein kinase 14, (4-benzylpiperidin-1-yl)[2-methoxy-4-(methylsulfanyl)phenyl]methanone (3 entities in total)
Functional Keywordsp38 map kinase inhibitors, sbdd, transferase
Biological sourceHomo sapiens (Human)
Total number of polymer chains1
Total formula weight45044.17
Authors
Lane, W.,Okada, K. (deposition date: 2018-08-22, release date: 2019-04-17, Last modification date: 2024-03-13)
Primary citationKaieda, A.,Takahashi, M.,Fukuda, H.,Okamoto, R.,Morimoto, S.,Gotoh, M.,Miyazaki, T.,Hori, Y.,Unno, S.,Kawamoto, T.,Tanaka, T.,Itono, S.,Takagi, T.,Sugimoto, H.,Okada, K.,Snell, G.,Bertsch, R.,Nguyen, J.,Sang, B.C.,Miwatashi, S.
Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 1.
Chemmedchem, 14:1022-1030, 2019
Cited by
PubMed 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.
PubMed: 30945818
DOI: 10.1002/cmdc.201900129
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.8 Å)
Structure validation

227561

數據於2024-11-20公開中

PDB statisticsPDBj update infoContact PDBjnumon