title: Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype.
abstract: High affinity and selective S1P(4) receptor (S1P(4)-R) small molecule agonists may be important proof-of-principle tools used to clarify the receptor biological function and effects to assess the therapeutic potential of the S1P(4)-R in diverse disease areas including treatment of viral infections and thrombocytopenia. A high-throughput screening campaign of the Molecular Libraries-Small Molecule Repository was carried out by our laboratories and identified (2Z,5Z)-5-((1-(2-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)-3-methyl-2-(methylimino) thiazolidin-4-one as a promising S1P(4)-R agonist hit distinct from literature S1P(4)-R modulators. Rational chemical modifications of the hit allowed the identification of a promising lead molecule with low nanomolar S1P(4)-R agonist activity and exquisite selectivity over the other S1P(1-3,5)-Rs family members. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the effects of the S1P(4)-R signaling cascade and elucidate the molecular basis of the receptor function.
authors: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
authors: Mariangela
authors: M
authors: Urbano
authors: Miguel
authors: M
authors: Guerrero
authors: Subash
authors: S
authors: Velaparthi
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: D006801:Humans; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000188:drug therapy
chemical_list: D049349:Receptors, Lysosphingolipid; D054852:Small Molecule Libraries; D045162:Thiazolidinediones