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

Abstract

Introduction: 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.

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

Expert opinion: 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.

Keywords::

• autoimmune diseases
• bradycardia
• fingolimod
• lymphopenia
• relapsing–remitting multiple sclerosis
• sphingosine-1-phosphate receptor agonists
• selective sphingosine-1-phosphate receptor agonists

Notes

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