Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists.
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.
Foss
Frank W
FW
Department of Chemistry, University of Virginia, McCormick Road, PO Box 400319, Charlottesville, VA 22904, USA. ff2185@columbia.edu
Snyder
Ashley H
AH
Davis
Michael D
MD
Rouse
Michael
M
Okusa
Mark D
MD
Lynch
Kevin R
KR
Macdonald
Timothy L
TL
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D006160:Guanosine Triphosphate / Q000378:metabolism; D007202:Indicators and Reagents; D008231:Lymphopenia / Q000139:chemically induced / Q000517:prevention & control; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D009904:Optical Rotation; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
D007202:Indicators and Reagents; D063065:Organophosphonates; D049349:Receptors, Lysosphingolipid; D006160:Guanosine Triphosphate