Sphingosine 1-phosphate receptor 1 agonists: a patent review (2013-2015)

Introduction: The sphingosine-1-phosphate (S1P) regulates diverse biological functions including cell proliferation, endothelial cell chemotaxis, angiogenesis, immune cell trafficking, mitogenesis, heart rate. The first-in-class S1P(1,3-5)-R pan-agonist fingolimod (FTY720) was approved by the FDA and EMEA for the treatment of relapsing-remitting multiple sclerosis, though the most common adverse effect is bradycardia which occurs in the early stage of treatment and resolves within the first 24h despite continuing treatment. The underlying mechanism of the cardiovascular effects is the activation of G-protein-gated inwardly rectifying potassium (GIRK) channel by the S1P(1)-R. Several second generation S1P(1)-R agonists with distinct selectivity, pharmacokinetics and safety profile from FTY720 are under development for the treatment of autoimmune and chronic inflammatory diseases. Areas covered: This review provides a summary of the patent literature from 2013 up to November 2015 on the S1P(1)-R agonist molecules and their relevant biological/pharmacological properties. Expert opinion: The molecules reviewed are S1P(1)-R agonists with a promising clinical outlook in particular in inflammation and autoimmune diseases. Clinical and preclinical studies of second generation S1P(1)-R agonists have been generating interesting results and may finally provide pharmacological agents with improved therapeutic profile than FTY720, particularly in terms of cardiovascular and pulmonary liabilities.