6OHD

P38 in complex with T-3220137

Summary for 6OHD

• Entry DOI: 10.2210/pdb6ohd/pdb
• Descriptor: Mitogen-activated protein kinase 14, 3-(3-tert-butyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-4-methyl-N-(1,2-oxazol-3-yl)benzamide (3 entities in total)
• Functional Keywords: sbdd, p38, kinase, protein binding, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 45080.10

Authors

Lane, W.,Saikatendu, K. (deposition date: 2019-04-05, release date: 2019-11-20, Last modification date: 2024-03-13)

Primary citation

Kaieda, 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.,Lane, W.,Sang, B.C.,Saikatendu, K.,Matsunaga, S.,Miwatashi, S.
Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]Pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 2.
Chemmedchem, 14:2093-2101, 2019

PubMed 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-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.

PubMed: 31697454
DOI: 10.1002/cmdc.201900373

Experimental method

X-RAY DIFFRACTION (2.5 Å)