3mw1
p38 kinase Crystal structure in complex with small molecule inhibitorp38 kinase Crystal structure in complex with small molecule inhibitor
Structural highlights
Publication Abstract from PubMedThe design, synthesis, and ability to inhibit p38alpha MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38alpha inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFalpha levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg). 1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase.,Lumeras W, Vidal L, Vidal B, Balague C, Orellana A, Maldonado M, Dominguez M, Segarra V, Caturla F J Med Chem. 2011 Nov 24;54(22):7899-910. Epub 2011 Oct 31. PMID:21999461[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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