Design, Synthesis, and Structure−Activity Relationships of Aminopyridine N-Oxides, a Novel Scaffold for the Potent and Selective Inhibition of p38 Mitogen Activated Protein Kinase

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• 作者：Wenceslao Lumeras ; Francisco Caturla ; Laura Vidal ; Cristina Esteve ; Cristina Balagu ; Adelina Orellana ; Mara Domnguez ; Ramn Roca ; Josep M. Huerta ; Nria Godessart ; Bernat Vidal
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：September 10, 2009
• 年：2009
• 卷：52
• 期：17
• 页码：5531-5545
• 全文大小：1086K
• 年卷期：v.52,no.17(September 10, 2009)
• ISSN：1520-4804

文摘

A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38α MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFα 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 a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38α inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFα levels in an acute murine model of inflammation (ED₅₀ = 1 mg/kg in LPS-induced TNFα production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED₅₀ = 4.5 mg/kg).