title: Sphingosine 1-phosphate receptor agonists: a patent review (2010-2012).
abstract: BACKGROUND
  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.
  
  
  METHODS
  This review provides the patent literature from 2010 to date on S1P-R agonist molecules and their relevant biological properties.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Scripps Research Institute, Department of Chemistry, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA. eroberts@scripps.edu
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
authors.forename: Miguel
authors.initials: M
authors.lastname: Guerrero
authors.forename: Mariangela
authors.initials: M
authors.lastname: Urbano
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000139:chemically induced; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology; D015195:Drug Design; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000503:physiopathology; D010330:Patents as Topic; D011409:Propylene Glycols / Q000009:adverse effects / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013110:Sphingosine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine