Sphingosine 1-phosphate receptor 1 agonists: a patent review (2013-2015). (2nd April 2016)

• Record Type: Journal Article
• Authors: Guerrero, Miguel; Urbano, Mariangela; Roberts, Edward
• Is Part Of: Expert opinion on therapeutic patents. Volume 26:Number 4(2016:Apr.)
• Page Start: 455
• Page End: 470
• Publication Date: 2016-04-02
• Subjects: Selective S1P1-R agonists -- FTY720 (fingolimod) -- bradycardia -- lymphopenia -- autoimmune and inflammatory diseases; Drugs -- Patents -- Periodicals; 615.10272
• DOI: 10.1517/13543776.2016.1157165
• Languages: English
• ISSNs: 1354-3776

Abstract

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 S1P1, 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.