title: Structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors: discovery of SphK1- and SphK2-selective inhibitors.
abstract: Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P1-5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2, and hence, inhibitors of this phosphorylation step are pivotal in understanding the physiological functions of SphKs. To date, SphK1 and 2 inhibitors with the potency, selectivity, and in vivo stability necessary to determine the potential of these kinases as therapeutic targets are lacking. Herein, we report the design, synthesis, and structure-activity relationship studies of guanidine-based SphK inhibitors bearing an oxadiazole ring in the scaffold. Our studies demonstrate that SLP120701, a SphK2-selective inhibitor (Ki = 1 μM), decreases S1P levels in histiocytic lymphoma (U937) cells. Surprisingly, homologation with a single methylene unit between the oxadiazole and heterocyclic ring afforded a SphK1-selective inhibitor in SLP7111228 (Ki = 48 nM), which also decreased S1P levels in cultured U937 cells. In vivo application of both compounds, however, resulted in contrasting effect in circulating levels of S1P. Administration of SLP7111228 depressed blood S1P levels while SLP120701 increased levels of S1P. Taken together, these compounds provide an in vivo chemical toolkit to interrogate the effect of increasing or decreasing S1P levels and whether such a maneuver can have implications in disease states.
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.
authors: Neeraj N
authors: NN
authors: Patwardhan
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.
authors: Emily A
authors: EA
authors: Morris
authors: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, United States.
authors: Yugesh
authors: Y
authors: Kharel
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.
authors: Mithun R
authors: MR
authors: Raje
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.
authors: Ming
authors: M
authors: Gao
authors: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, United States.
authors: Jose L
authors: JL
authors: Tomsig
authors: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, United States.
authors: Kevin R
authors: KR
authors: Lynch
authors: Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.
authors: Webster L
authors: WL
authors: Santos
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019791:Guanidine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099157:Sphingosine Kinase
chemical_list: D019791:Guanidine; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D000099157:Sphingosine Kinase; C000594250:sphingosine kinase 2, human
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