title: Sphingosine 1-phosphate analogs as receptor antagonists.
abstract: Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cell and tissue responses via a set of cell surface receptors. The recent development of S1P receptor agonists, led by the immunomodulatory pro-drug FTY720, has revealed that S1P signaling is an important regulator of lymphocyte trafficking. With the twin goals of understanding structure-activity relationships of S1P ligands and developing tool compounds to explore S1P biology, we synthesized and tested numerous S1P analogs. We report herein that a subset of our aryl amide-containing compounds are antagonists at the S1P(1) and S1P(3) receptors. The lead compound in series, VPC23019, was found in broken cell and whole cell assays to behave as a competitive antagonist at the S1P(1) and S1P(3) receptors. The structure-activity relationship of this series is steep; for example, a slight modification of the lead compound resulted in VPC25239, which was one log order more potent at the S1P(3) receptor. These new chemical entities will enable further understanding of S1P signaling and provide leads for further S1P receptor antagonist development.
authors.affiliation: Biochemistry and Molecular Genetics, Pharmacology, and Chemistry, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Davis
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Clemens
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Macdonald
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
mesh_terms: D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000068876:Fingolimod Hydrochloride; D006160:Guanosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008214:Lymphocytes / Q000378:metabolism; D008246:Lysophospholipids / Q000737:chemistry* / Q000494:pharmacology*; D008956:Models, Chemical; D010768:Phosphoserine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology; D011485:Protein Binding; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D008024:Ligands; D008055:Lipids; D008246:Lysophospholipids; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C000611541:VPC23019; D010768:Phosphoserine; C060506:sphingosine 1-phosphate; D006160:Guanosine Triphosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002118:Calcium