Synthesis of benzimidazole based analogues of sphingosine-1-phosphate: discovery of potent, subtype-selective S1P4 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. A member of this receptor family, S1P4, is highly and almost exclusively expressed in the lymphoid system and has been implicated in regulation of cell shape and motility. This report describes the synthesis of several potent benzimidazole based S1P4 receptor selective agonists. For instance, compound 9b displayed an EC50 = 36 nM at the S1P4 receptor using a [γ-35S]GTP binding assay as compared to an EC50 = 37 nM for the endogenous ligand. We also report the effects of altering stereochemistry at the C2 position, methylation at the C1 and C2 position, and activity differences between the alcohol and phosphate head groups of the analogues.