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 S1P(1) receptor using a [gamma-S-35]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 S1P(2) and increased agonism at S1P(5). (C) 2003 Elsevier Ltd. All rights reserved.