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

J Med Chem. 2010 Apr 8;53(7):2766-78. doi: 10.1021/jm901860h.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Amidines
  • Enzyme Inhibitors
  • Oxadiazoles
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine