Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists

Bioorg Med Chem. 2007 Jan 15;15(2):663-77. doi: 10.1016/j.bmc.2006.10.060. Epub 2006 Nov 1.


The synthesis of N-arylamide phosphonates and related arylether and arylamine analogues provided potent, subtype-selective agonists and antagonists of the five known sphingosine 1-phosphate (S1P) receptors (S1P(1-5)). To this end, the syntheses of phosphoserine mimetics-selectively protected and optically active phosphonoserines-are described. In vitro binding assays showed that the implementation of phosphonates as phosphate mimetics provided compounds with similar receptor binding affinities as compared to their phosphate precursors. meta-substituted arylamide phosphonates were discovered to be antagonists of the S1P(1) and S1P(3) receptors. When administered to mice, an antagonist blocked the lymphopenia evoked by a S1P receptor agonist and caused capillary leakage in both lung and kidney.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Capillary Permeability / drug effects
  • Cell Line
  • Guanosine Triphosphate / metabolism
  • Indicators and Reagents
  • Lymphopenia / chemically induced
  • Lymphopenia / prevention & control
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Inbred C57BL
  • Molecular Conformation
  • Optical Rotation
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / pharmacology*
  • Receptors, Lysosphingolipid / agonists*
  • Receptors, Lysosphingolipid / antagonists & inhibitors*
  • Tissue Distribution


  • Indicators and Reagents
  • Organophosphonates
  • Receptors, Lysosphingolipid
  • Guanosine Triphosphate