Discovery, Biological Evaluation, and Structure−Activity Relationship of Amidine Based Sphingosine Kinase Inhibitors

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• 作者：Thomas P. Mathews ; Andrew J. Kennedy ; Yugesh Kharel ; Perry C. Kennedy ; Oana Nicoara ; Manjula Sunkara ; Andrew J. Morris ; Brian R. Wamhoff ; Kevin R. Lynch ; Timothy L. Macdonald
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 8, 2010
• 年：2010
• 卷：53
• 期：7
• 页码：2766-2778
• 全文大小：1053K
• 年卷期：v.53,no.7(April 8, 2010)
• ISSN：1520-4804

文摘

Sphingosine 1-phosphate (S1P), a potent phospholipid growth and trophic factor, is synthesized in vivo by two sphingosine kinases. Thus these kinases have been proposed as important drug targets for treatment of hyperproliferative diseases and inflammation. We report here a new class of amidine-based sphingosine analogues that are competitive inhibitors of sphingosine kinases exhibiting varying degrees of enzyme selectivity. These inhibitors display K_I values in the submicromolar range for both sphingosine kinases and, in cultured vascular smooth muscle cells, decrease S1P levels and initiate growth arrest.