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 I-phosphate (SIP) 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 SIP receptor agonist and caused capillary leakage in both lung and kidney. (c) 2006 Elsevier Ltd. All rights reserved.