title: 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.
authors.affiliation: University of Virginia, Department of Chemistry, P.O. Box 400319, McCormick Road, Charlottesville, Virginia 22904, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Mathews
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kennedy
authors.forename: Yugesh
authors.initials: Y
authors.lastname: Kharel
authors.forename: Perry C
authors.initials: PC
authors.lastname: Kennedy
authors.forename: Oana
authors.initials: O
authors.lastname: Nicoara
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wamhoff
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Macdonald
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D010069:Oxadiazoles / Q000737:chemistry; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D013110:Sphingosine / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000099157:Sphingosine Kinase
chemical_list: D000578:Amidines; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase