Sphingosine-1-phosphate (S1P) acts as an extracellular ligand for the sphingosine-1-phosphate G-protein coupled receptors (S1P1-5).  S1P1 agonism induces receptor internalization, which attenuates T-cell response to S1P gradients, preventing their egress from secondary lymphoid tissues.  S1P5 receptor is predominantly expressed in oligodendrocytes and may contribute to remyelination, whereas activation of S1P3 has been reported to cause heart rate reduction and pulmonary epithelial leakage.A non selective S1P receptor agonist, FTY720 (GilenyaTM) was approved for the treatment of relapsing remitting multiple sclerosis.  The 2nd generation of selective S1P1 agonists and S1P1/5 agonists are in clinical development.This presentation will detail the discovery and SAR of a potent and selective series of benzimidazole based S1P1/5 agonists.  ASP4058 discovered from this series demonstrated efficacy when administered orally in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.

Discovery of ASP4058, a potent and selective sphingosine-1-phosphate receptor 1 and 5 agonist

246th National Meeting (2013)

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