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

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-base...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-04, Vol.53 (7), p.2766-2778
Main Authors: Mathews, Thomas P, Kennedy, Andrew J, Kharel, Yugesh, Kennedy, Perry C, Nicoara, Oana, Sunkara, Manjula, Morris, Andrew J, Wamhoff, Brian R, Lynch, Kevin R, Macdonald, Timothy L
Format: Article
Language:English
Subjects:
Amidines - chemical synthesis
Amidines - chemistry
Amidines - pharmacology
Animals
Cell Proliferation - drug effects
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Mice
Myocytes, Smooth Muscle - cytology
Myocytes, Smooth Muscle - drug effects
Oxadiazoles - chemistry
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) - chemistry
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Protein Structure, Tertiary
Rats
Sphingosine - metabolism
Structure-Activity Relationship
Substrate Specificity
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm901860h