title: Discovery and optimization of 1,3,4-trisubstituted-pyrazolone derivatives as novel, potent, and nonsteroidal farnesoid X receptor (FXR) selective antagonists.
abstract: LBVS of 12480 in-house compounds, followed by HTRF assay, resulted in one nonsteroidal compound (11) with antagonistic activity against FXR (69.01 ± 11.75 μM). On the basis of 11, 26 new derivatives (12a-z) were designed and synthesized accordingly. Five derivatives (12f-g, 12p, 12u, and 12y) showed better antagonistic activities against FXR than compound 11. Remarkably, the most potent derivative, 12u (8.96 ± 3.62 μM), showed antagonistic capability approximately 10 times and 8-fold higher than that of the control (GS) and the starting compound 11, respectively. 12u was further confirmed to have high binding affinity with FXRαLBD, FXR specificity over six other nuclear receptors, and potent antagonistic activity against FXR in two cell testing platforms. 12u strongly suppressed the regulating effects of CDCA on FXR target genes. The therapeutic potential of 12u was identified by lowering the contents of triglyceride and cholesterol in human hepatoma HepG2 cells and in the cholesterol-fed C57BL/6 mices.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Zhenting
authors.initials: Z
authors.lastname: Gao
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chenjing
authors.initials: C
authors.lastname: Li
authors.forename: Xing
authors.initials: X
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Jin
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Yan
authors.forename: Ruoqun
authors.initials: R
authors.lastname: Ma
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D062126:Databases, Chemical; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014280:Triglycerides / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000924:Anticholesteremic Agents; D001597:Benzylidene Compounds; D002635:Chenodeoxycholic Acid; D002784:Cholesterol; D011720:Pyrazoles; D047069:Pyrazolones; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C576399:4-(4-hydroxy-3-methoxybenzylidene)-1-(3-nitrophenyl)-3-phenyl-1H-pyrazol-5(4H)-one