Synthesis, stability, and implications of phosphothioate agonists of sphingosine-1-phosphate receptors.
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.
Foss
Frank W
FW
Department of Chemistry, University of Virginia, McCormick Road, PO Box 400319, Charlottesville, VA 22904, USA. fwf4b@virginia.edu
Clemens
Jeremy J
JJ
Davis
Michael D
MD
Snyder
Ashley H
AH
Zigler
Molly A
MA
Lynch
Kevin R
KR
Macdonald
Timothy L
TL
D009682:Magnetic Resonance Spectroscopy; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013873:Thionucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D049349:Receptors, Lysosphingolipid; D013873:Thionucleotides