Synthesis and biological evaluation of γ-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 (S1P1–5). 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 S1P1 and S1P3 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.

Arylamide, arylether, and arylamine containing γ-aminophosphonates provided potent, subtype-selective agonists and antagonists of the sphingosine 1-phosphate receptors. These phosphate mimetics displayed binding affinities comparable with previously reported phosphate precursors. Two pathways, from glycidol and serine, were pursued for the synthesis of the intermediate phosphonoserine.Figure optionsDownload as PowerPoint slide