TY - JOUR
T1 - Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors
AU - Mathews, Thomas P.
AU - Kennedy, Andrew J.
AU - Kharel, Yugesh
AU - Kennedy, Perry C.
AU - Nicoara, Oana
AU - Sunkara, Manjula
AU - Morris, Andrew J.
AU - Wamhoff, Brian R.
AU - Lynch, Kevin R.
AU - MacDonald, Timothy L.
PY - 2010/4/8
Y1 - 2010/4/8
N2 - 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.
AB - 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.
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U2 - 10.1021/jm901860h
DO - 10.1021/jm901860h
M3 - Article
C2 - 20205392
AN - SCOPUS:77950557394
SN - 0022-2623
VL - 53
SP - 2766
EP - 2778
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -