title: Discovery, design and synthesis of novel potent and selective sphingosine-1-phosphate 4 receptor (S1P₄-R) agonists.
abstract: High affinity and selective small molecule agonists of the S1P(4) receptor (S1P(4)-R) may have significant therapeutic utility in diverse disease areas including autoimmune diseases, viral infections and thrombocytopenia. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 3-(2-(2,4-dichlorophenoxy)ethoxy)-6-methyl-2-nitropyridine as a moderately potent and selective S1P(4)-R hit agonist. Design, synthesis and systematic structure-activity relationships study of the HTS-derived hit led to the development of novel potent S1P(4)-R agonists exquisitely selective over the remaining S1P(1-3,5)-Rs family members. Remarkably, the molecules herein reported provide novel pharmacological tools to decipher the biological function and assess the therapeutic utility of the S1P(4)-R.
authors: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States.
authors: Miguel
authors: M
authors: Guerrero
authors: Mariangela
authors: M
authors: Urbano
authors: Jian
authors: J
authors: Zhao
authors: Melissa
authors: M
authors: Crisp
authors: Peter
authors: P
authors: Chase
authors: Peter
authors: P
authors: Hodder
authors: Marie-Therese
authors: MT
authors: Schaeffer
authors: Steven
authors: S
authors: Brown
authors: Hugh
authors: H
authors: Rosen
authors: Edward
authors: E
authors: Roberts
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003713:Dendritic Cells / Q000166:cytology; D015195:Drug Design; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008956:Models, Chemical; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid