title: Synthesis, stability, and implications of phosphothioate agonists of sphingosine-1-phosphate receptors.
abstract: Phosphothioates may provide metabolic stability when compared to their phosphate counterparts, while retaining the potency and efficacy as agonists at sphingosine-1-phosphate (S1P) G-protein coupled receptors. Unlike their phosphate precursors, phosphothioate compounds with S1P-receptor profiles similar to that of FTY720, an emerging immunomodulator, were shown to evoke prolonged lymphopenia in vivo. Analysis of mouse plasma concentrations for a series of related alcohol/phosphate/phosphothioate compounds showed the conversion of the phosphate to alcohol. These preliminary data highlight the importance of metabolic regulation of S1P receptor ligands.
authors.affiliation: Department of Chemistry, University of Virginia, McCormick Road, PO Box 400319, Charlottesville, VA 22904, USA. fwf4b@virginia.edu
authors.forename: Frank W
authors.initials: FW
authors.lastname: Foss
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Clemens
authors.forename: Michael D
authors.initials: MD
authors.lastname: Davis
authors.forename: Ashley H
authors.initials: AH
authors.lastname: Snyder
authors.forename: Molly A
authors.initials: MA
authors.lastname: Zigler
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Macdonald
mesh_terms: D009682:Magnetic Resonance Spectroscopy; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013873:Thionucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D049349:Receptors, Lysosphingolipid; D013873:Thionucleotides