title: Synthesis of benzimidazole based analogues of sphingosine-1-phosphate: discovery of potent, subtype-selective S1P4 receptor agonists.
abstract: Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid with the capacity to induce a broad range of cellular responses via its interaction with the S1P family of G-protein coupled receptors. A member of this receptor family, S1P(4), is highly and almost exclusively expressed in the lymphoid system and has been implicated in regulation of cell shape and motility. This report describes the synthesis of several potent benzimidazole based S1P(4) receptor selective agonists. For instance, compound 9b displayed an EC(50)=36 nM at the S1P(4) receptor using a [gamma-(35)S]GTP binding assay as compared to an EC(50)=37 nM for the endogenous ligand. We also report the effects of altering stereochemistry at the C2 position, methylation at the C1 and C2 position, and activity differences between the alcohol and phosphate head groups of the analogues.
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, VA 22903, USA. clemens@chem.ucla.edu
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Clemens
authors.forename: Michael D
authors.initials: MD
authors.lastname: Davis
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Macdonald
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis*; D006801:Humans; D008246:Lysophospholipids / Q000138:chemical synthesis*; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine