title: A benzo[b]thiophene-based selective type 4 S1P receptor agonist.
abstract: S1P receptors (S1PR1-5) are a group of GPCRs activated by a high affinity binding with S1P that have important roles in the regulation of the immune system. A potent S1PR agonist FTY720 is an immunomodulator used to treat multiple sclerosis and several 'second generation' drugs are under clinical development. Subtype-selective agonists have been reported for each S1PR isotype, some of which are used as pharmacological tools for functional studies. Here we report the discovery and initial characterization of compound 5c, a benzo[b]thiophene amino carboxylate which exhibits potent and selective agonist activity for S1PR4. Compound 5c has an EC50=200nM as an agonist in GTPγ35S binding assay for S1PR4 and exhibits no activity against S1PR1,2,3,5. We confirmed its potent activity and decent S1PR subtype selectivity using biochemical and cellular assays.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, 360 Longwood Avenue, Boston, MA 02215, USA.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, 360 Longwood Avenue, Boston, MA 02215, USA. Electronic address: Nathanael_Gray@dfci.harvard.edu.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D049349:Receptors, Lysosphingolipid; D013876:Thiophenes; C088015:benzothiophene
keywords: S1P receptor; S1P4; S1PR4; Selective agonist; Sphingosine-1-phosphate