Discovery and Optimization of 1,3,4-Trisubstituted-pyrazolone Derivatives as Novel, Potent, and Nonsteroidal Farnesoid X Receptor (FXR) Selective Antagonists
Discovery and Optimization of 1,3,4-Trisubstituted-pyrazolone Derivatives as Novel, Potent, and Nonsteroidal Farnesoid X Receptor (FXR) Selective Antagonists
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1,3,4-三取代吡唑啉酮衍生物的发现和优化，作为新型、有效的非甾体法尼醇 X 受体 (FXR) 选择性拮抗剂
DOI：
10.1021/jm3002718
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发表时间：
2012-08-23
影响因子：
7.3
通讯作者：
Li, Jian
中科院分区：
文献类型：
--
作者：
Huang, Huang;Yu, Ying;Li, Jian
对12480种内部化合物进行LBVS，然后进行HTRF测定，得到一种对FXR具有拮抗活性的非甾体化合物（11）（69.01 +/- 11.75 μ M）。在11的基础上，设计合成了26个新的衍生物（12 a-z）。五个衍生物（12 f-g、12 p、12 u和12 y）显示出比化合物11更好的对FXR的拮抗活性。值得注意的是，最有效的衍生物12 u（8.96 +/- 3.62 μ M）显示的拮抗能力分别比对照（GS）和起始化合物11高约10倍和8倍。在两个细胞测试平台中，进一步证实12 u与FXR α LBD具有高结合亲和力，FXR特异性超过其他六种核受体，并且对FXR具有强效拮抗活性。12 u强烈抑制CDCA对FXR靶基因的调节作用。通过降低人肝癌HepG 2细胞和高胆固醇喂养的C57 BL/6小鼠的甘油三酯和胆固醇含量来鉴定12 u的治疗潜力。
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 mu M). 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 mu M), 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 FXR alpha LBD, 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.