title: Pyrazolidine-3,5-dione derivatives as potent non-steroidal agonists of farnesoid X receptor: virtual screening, synthesis, and biological evaluation.
abstract: The identification of a novel pyrazolidine-3,5-dione based scaffold hit compound as Farnesoid X receptor (FXR) partial or full agonist has been accomplished by means of virtual screening techniques. A series of pyrazolidine-3,5-dione derivatives (1a-u and 7) was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activities against FXR. Most of them showed agonistic potencies and 10 of them (1a, 1b, 1d-f, 1j, 1n, 1t, 5b, and 7) exhibited lower EC(50) values than the reference drug CDCA. Molecular modeling studies for the representative compounds 1a, 1d, 1f, 1j, 1n, 1u, 5b, and 7 were also presented. The novel structural scaffold has provided a new direction for finding potent and selective FXR partial and full agonists (referred to as 'selective bile acid receptor modulators', SBARMs).
authors.affiliation: Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School of the Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Deng
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008156:Luciferases / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry; D014157:Transcription Factors / Q000819:agonists* / Q000737:chemistry; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D008024:Ligands; D008156:Luciferases; D011720:Pyrazoles; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C443742:pyrazolidine-3,5-dione