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Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors.

ABSTRACT: 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.

SUBMITTER: Mathews TP

PROVIDER: S-EPMC2875079 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors.

Mathews Thomas P TP Kennedy Andrew J AJ Kharel Yugesh Y Kennedy Perry C PC Nicoara Oana O Sunkara Manjula M Morris Andrew J AJ Wamhoff Brian R BR Lynch Kevin R KR Macdonald Timothy L TL

Journal of medicinal chemistry 20100401 7

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 bot ...[more]

PMID: 20205392

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