3ROC

Crystal structure of human p38 alpha complexed with a pyrimidinone compound

Summary for 3ROC

• Entry DOI: 10.2210/pdb3roc/pdb
• Descriptor: Mitogen-activated protein kinase 14, 3-{5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl}-N-(2-hydroxyethyl)-4-methylbenzamide, 4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine, ... (4 entities in total)
• Functional Keywords: transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): Q16539
• Total number of polymer chains: 1
• Total formula weight: 42032.28

Authors

Shieh, H.-S.,Xing, L. (deposition date: 2011-04-25, release date: 2011-06-15, Last modification date: 2024-02-28)

Primary citation

Devadas, B.,Selness, S.R.,Xing, L.,Madsen, H.M.,Marrufo, L.D.,Shieh, H.,Messing, D.M.,Yang, J.Z.,Morgan, H.M.,Anderson, G.D.,Webb, E.G.,Zhang, J.,Devraj, R.V.,Monahan, J.B.
Substituted N-aryl-6-pyrimidinones: A new class of potent, selective, and orally active p38 MAP kinase inhibitors.
Bioorg.Med.Chem.Lett., 21:3856-3860, 2011

PubMed Abstract: A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (>90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-α in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model.

PubMed: 21620699
DOI: 10.1016/j.bmcl.2011.05.006

Experimental method

X-RAY DIFFRACTION (1.7 Å)