1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase

详细信息    查看全文

• 作者：Wenceslao Lumeras ; Laura Vidal ; Bernat Vidal ; Cristina Balagu茅 ; Adelina Orellana ; M贸nica Maldonado ; Mar铆a Dom铆nguez ; V铆ctor Segarra ; Francisco Caturla
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 24, 2011
• 年：2011
• 卷：54
• 期：22
• 页码：7899-7910
• 全文大小：509K
• 年卷期：v.54,no.22(November 24, 2011)
• ISSN：1520-4804

文摘

The design, synthesis, and ability to inhibit p38伪 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 TNF伪 production in human whole blood. Structure鈥揳ctivity 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 p38伪 inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNF伪 levels in an acute murine model of inflammation (ED₅₀ = 0.5 mg/kg in LPS-induced TNF伪 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 (ED₅₀ < 1 mg/kg).