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

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

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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 KI values in the submicromolar range for both sphingosine kinases and, in cultured vascular smooth muscle cells, decrease S1P levels and initiate growth arrest.

Original languageEnglish (US)
Pages (from-to)2766-2778
Number of pages13
JournalJournal of Medicinal Chemistry
Volume53
Issue number7
DOIs
StatePublished - Apr 8 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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