Discovery and Optimization of 1,3,4-Trisubstituted-pyrazolone Derivatives as Novel, Potent, and Nonsteroidal Farnesoid X Receptor (FXR) Selective Antagonists

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...

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Veröffentlicht in:	Journal of medicinal chemistry 2012-08, Vol.55 (16), p.7037-7053
Hauptverfasser:	Huang, Huang, Yu, Ying, Gao, Zhenting, Zhang, Yong, Li, Chenjing, Xu, Xing, Jin, Hui, Yan, Wenzhong, Ma, Ruoqun, Zhu, Jin, Shen, Xu, Jiang, Hualiang, Chen, Lili, Li, Jian
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Anticholesteremic Agents - chemical synthesis Anticholesteremic Agents - chemistry Anticholesteremic Agents - pharmacology Benzylidene Compounds - chemical synthesis Benzylidene Compounds - chemistry Benzylidene Compounds - pharmacology Biological Availability Chenodeoxycholic Acid - pharmacology Cholesterol - metabolism Databases, Chemical HEK293 Cells Hep G2 Cells Humans Liver - metabolism Male Mice Mice, Inbred C57BL Models, Molecular Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Pyrazolones - chemical synthesis Pyrazolones - chemistry Pyrazolones - pharmacology Rats Receptors, Cytoplasmic and Nuclear - agonists Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors Receptors, Cytoplasmic and Nuclear - genetics Solubility Stereoisomerism Structure-Activity Relationship Transcription, Genetic Transcriptional Activation Triglycerides - metabolism
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