Synthesis of para-Alkyl aryl amide analogues of sphingosine-1-phosphate: discovery of potent S1P receptor agonists

Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid with the capacity to induce a broad range of cellular responses via its interaction with the S1P family of G-protein coupled receptors. This report describes the synthesis of several potent S1P receptor agonists. For instance, compound 9c displayed an EC50=8.6 nM at the S1P1 receptor using a [γ-35S]GTP binding assay as compared to an EC50=4.5 nM for the endogenous ligand. We also report the effects associated with introduction of a phenyl ring between the ‘linker’ and ‘lipophilic tail’ regions of the analogues, for example total loss of activity at S1P2 and increased agonism at S1P5.