Synthetic sphingosine 1-phosphate receptor modulators--opportunities and potential pitfalls

Sphingosine 1-phosphate (S1P) evokes a plethora of physiological responses by stimulating members of a G protein-coupled receptor family, known as S1P receptors. Currently five different mammalian S1P receptor subtypes, S1P₁₋₅, each with a different cellular expression pattern, were identified. The S1P₁ receptor in particular has attracted major interest throughout the pharmaceutical industry following the breakthrough discovery that this S1P receptor subtype is critically involved in the regulation of lymphocyte trafficking through secondary lymphoid organs. Since then, examples of synthetic S1P₁ agonists with lymphocyte reducing and immunomodulating activity demonstrated efficacy in numerous preclinical models of autoimmune disease and transplantation. Notably FTY720 (fingolimod), a pro-drug that is phosphorylated in vivo and converted into a non-selective S1P₁,₃,₄,₅ receptor agonist, has been widely used to increase the understanding of S1P₁ receptor biology. Results from recently completed phase III clinical trials using FTY720 paved the way for this non-selective S1P₁ receptor agonist to become the first oral therapy in multiple sclerosis, with potential expansion into many other autoimmune diseases. This review briefly outlines the field of S1P₁ receptor biology and summarizes recent approaches in medicinal chemistry to discover potent and selective S1P₁ receptor agonists. In particular, the complexity of discovering a molecule akin to FTY720 but with an improved side-effect profile will be discussed.