S1P receptor agonists lead to sequestration of circulating lymphocytes to lymphoid organs and prevent these immune cells from causing inflammation and tissue damage. S1P receptor agonists therefore have great therapeutic potential to treat autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or psoriasis. Indeed, a pro-drug of a non selective S1P receptor agonist, FTY720 (GilenyaTM) is an approved treatment for relapsing remitting multiple sclerosis. Attention has focused on dissecting the pharmacological effects conveyed by the five known S1P receptors. Experiments with S1P1 receptor knock-out mice and S1P1 selective agonists demonstrated that targeting S1P1 is necessary and sufficient to cause lymphocyte sequestration to lymphoid organs. S1P5 agonism maintains immunoquiescence in the brain and may contribute to remyelination, whereas activation of the S1P3 pathway has been reported to cause heart rate reduction, vaso- and bronchoconstriction, and pulmonary epithelial leakage.To date, a number of selective S1P1 and S1P1/5 receptor agonists are in clinical development for multiple sclerosis and other diseases. Despite being selective against S1P3, several of these compounds have been reported to cause first dose effects on heart rate in humans.  Here, we will present our efforts to evolve the structure of our HTS hit 1  ?into a compound suitable for clinical development. Key questions driving our drug discovery program were the compounds' stability, their S1P receptor selectivity profile as well as means to avoid the first dose effect on heart rate.

Toward the discovery of novel, orally active S1P<sub>1</sub>-selective receptor agonists

245th National Meeting (2013)

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Toward the discovery of novel, orally active S1P1-selective receptor agonists

Toward the discovery of novel, orally active S1P₁-selective receptor agonists