title: Sphingosine 1-phosphate receptor 1 agonists: a patent review (2013-2015).
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Department of Chemistry , The Scripps Research Institute , La Jolla , CA 92037 , USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Guerrero
authors.affiliation: a Department of Chemistry , The Scripps Research Institute , La Jolla , CA 92037 , USA.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Urbano
authors.affiliation: a Department of Chemistry , The Scripps Research Institute , La Jolla , CA 92037 , USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000473:pathology; D015195:Drug Design; D000068876:Fingolimod Hydrochloride / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000503:physiopathology; D010330:Patents as Topic; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: FTY720 (fingolimod); Selective S1P1-R agonists; autoimmune and inflammatory diseases; bradycardia; lymphopenia