Synthesis, Crystal Structure, and Activity of Pyrazole-Based Inhibitors of p38 Kinase

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• 作者：Matthew J. Graneto ; Ravi G. Kurumbail ; Michael L. Vazquez ; Huey-Sheng Shieh ; Jennifer L. Pawlitz ; Jennifer M. Williams ; William C. Stallings ; Lifeng Geng ; Ashok S. Naraian ; Francis J. Koszyk ; Michael
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 15, 2007
• 年：2007
• 卷：50
• 期：23
• 页码：5712 - 5719
• 全文大小：644K
• 年卷期：v.50,no.23(November 15, 2007)
• ISSN：1520-4804

文摘

A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a bindingmodel based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietaneswas developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log Dwas used in tandem with structure-based design to guide medicinal chemistry strategy and improve the invivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complexwith p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the moleculeinduces an interaction with Asp112 of p38. A compound identified from this series was efficacious in ananimal model of rheumatic disease.