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

ABSTRACT

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 24 h despite continuing treatment. The underlying mechanism of the cardiovascular effects is the activation of G-protein-gated inwardly rectifying potassium (GIRK) channel by the S1P₁-R. Several second generation S1P₁-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 S1P₁-R agonist molecules and their relevant biological/pharmacological properties.

Expert opinion: The molecules reviewed are S1P₁-R agonists with a promising clinical outlook in particular in inflammation and autoimmune diseases. Clinical and preclinical studies of second generation S1P₁-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.

KEYWORDS:

• Selective S1P₁-R agonists
• FTY720 (fingolimod)
• bradycardia
• lymphopenia
• autoimmune and inflammatory diseases

Article highlights

• Essential biological processes and therapeutic applications of S1P₁-R agonists are described.

• Clinical benefits and limitations of the first-in-class immunosuppressant FTY720 (fingolimod) are discussed.

• A review of the patent literature on S1P₁-R agonists over the past three years is provided.

• Most research groups have been pursuing S1P₃-R sparing S1P₁-R agonists with improved safety profile than FTY720, particularly with respect to cardiovascular and pulmonary liabilities.

• Clinical studies will determine whether the new S1P₁-R agonists improve the safety profile of FTY720.

This box summarizes key points contained in the article.

Declaration of interest

This paper has been supported by The Scripps Research Institute, La Jolla, CA. M Guerrero and E Roberts have financial interest in Ozanimod. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.