Sphingosine 1-phosphate receptor agonists: a patent review (2010-2012)

The sphingosine-1-phosphate (S1P)-driven signaling regulates fundamental biological functions, including cell proliferation, angiogenesis, endothelial cell chemotaxis, immune cell trafficking and mitogenesis. A large body of research has been focusing on the development of immunosuppressive S1P1 receptor (S1P1-R) agonist molecules. The S1P(1,3-5)-R pan-agonist fingolimod (FTY720) has been approved by the FDA for the treatment of relapsing-remitting multiple sclerosis. However, FTY720 is now contraindicated in patients with compromised cardiac function. Although the main adverse effect bradycardia has been linked to the S1P3-R activation, cardiovascular liabilities persist with more selective S1P1-R agonists that have entered clinical trials. In contrast to the S1P1-R, the therapeutic application of the S1P(2-5)-Rs remains poorly explored.

This review provides the patent literature from 2010 to date on S1P-R agonist molecules and their relevant biological properties.

Limited progress has been made on agonists at S1P(4,5)-R subtypes, with some families of S1P5-R agonists showing promising results in animal models of age-related cognitive disorders. A discrete number of reviewed molecules are S1P1-R agonists with a promising clinical outlook in transplantation, inflammation, cancer and autoimmune settings. Further preclinical and clinical studies will determine whether the new developed S1P1-R agonists do indeed improve the safety profile of FTY720.