Synthesis, stability, and implications of phosphothioate agonists of sphingosine-1-phosphate receptors

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 20; pp. 4470 - 4474
• Main Authors: Foss, Frank W., Clemens, Jeremy J., Davis, Michael D., Snyder, Ashley H., Zigler, Molly A., Lynch, Kevin R., Macdonald, Timothy L.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.10.2005; Elsevier
• Subjects: Biological and medical sciences; Immunomodulators; Lymphopenia; Magnetic Resonance Spectroscopy; Medical sciences; Pharmacology. Drug treatments; Phosphothioate; Receptors, Lysosphingolipid - agonists; Sphingosine-1-phosphate; Thionucleotides - chemical synthesis; Thionucleotides - chemistry; Thionucleotides - pharmacology; Lymphopenia; Phosphothioate; Sphingosine-1-phosphate; Biological fluid; Agonist; Toxicity; Hemopathy; Blood; Sphingosine-1 -phosphate; Structure activity relation; Chemical synthesis; Lymphocytopenia; G protein; Aminoamide; Aliphatic compound; Rodentia; Phospholhioate; Bioavailability; In vitro; Immunomodulator; In vivo; Hydrolysis resistance; Vertebrata; Mammalia; Mouse; Animal; Benzene; Organic phosphorus compounds; Affinity; Immunosuppressive agent; Pharmacokinetics; Primary amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.07.057

The synthesis and biological activity of phosphothioates, as subtype selective sphingosine-1-phosphate receptor agonists, are described. Sphingosine-1-phosphate receptor agonist 12 is degraded to its alcohol in vivo. Compared to their phosphate precursors, phosphothioate compounds 7 and 13 were shown to induce lymphopenia for protracted intervals in vivo. 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.