title: Discovery, design and synthesis of the first reported potent and selective sphingosine-1-phosphate 4 (S1P4) receptor antagonists.
abstract: Selective S1P(4) receptor antagonists could be novel therapeutic agents for the treatment of influenza infection in addition to serving as a useful tool for understanding S1P(4) receptor biological functions. 5-(2,5-Dichlorophenyl)-N-(2,6-dimethylphenyl)furan-2-carboxamide was identified from screening the Molecular Libraries-Small Molecule Repository (MLSMR) collection and selected as a promising S1P(4) antagonist hit with moderate in vitro potency and high selectivity against the other family receptor subtypes (S1P(1-3,5)). Rational chemical modifications of the hit allowed the disclosure of the first reported highly selective S1P(4) antagonists with low nanomolar activity and adequate physicochemical properties suitable for further lead-optimization studies.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States.
authors.forename: Miguel
authors.initials: M
authors.lastname: Guerrero
authors.forename: Mariangela
authors.initials: M
authors.lastname: Urbano
authors.forename: Subash
authors.initials: S
authors.lastname: Velaparthi
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Schaeffer
authors.forename: Steven
authors.initials: S
authors.lastname: Brown
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D000998:Antiviral Agents; D005663:Furans; D049349:Receptors, Lysosphingolipid