Identification of a lead pharmacophore for the development of potent nuclear receptor modulators as anticancer and X syndrome disease therapeutic agents.
Identification of a lead pharmacophore for the development of potent nuclear receptor modulators as anticancer and X syndrome disease therapeutic agents.
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DOI：
10.1002/chin.200651218
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发表时间：
2006-08
影响因子：
2.7
通讯作者：
Hsiang-Ru Lin;D. Abraham
中科院分区：
文献类型：
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作者：
Hsiang-Ru Lin;D. Abraham
设计、合成了一系列四氢异喹啉-N-苯酰胺衍生物，并测定了它们对雄激素受体（AR）的相对亲和力和拮抗活性。化合物1b（相对结合亲和力RBA = 6.4）和1h（RBA = 12.6）的结合亲和力高于一种有效的AR拮抗剂fluclide（RBA = 1）。这两种化合物也发挥了最佳的拮抗活性，对AR的报告试验。还测试了衍生物对另一种核受体法尼醇X受体（FXR）的活性，其中大多数化合物充当弱拮抗剂，然而，化合物1h充当FXR激动剂，其活性略低于鹅去氧胆酸（CDCA）（天然FXR激动剂）的活性。
A series of tetrahydroisoquinoline-N-phenylamide derivatives were designed, synthesized, and tested for their relative binding affinity and antagonistic activity against androgen receptor (AR). Compound 1b (relative binding affinity, RBA = 6.4) and 1h (RBA = 12.6) showed higher binding affinity than flutamide (RBA = 1), a potent AR antagonist. These two compounds also exerted optimal antagonistic activity against AR in reporter assays. The derivatives were also tested for their activities against another nuclear receptor, farnesoid x receptor (FXR), with most compounds acting as weak antagonists, however, compound 1h behaved as a FXR agonist with activity slightly less than that of chenodeoxycholic acid (CDCA), a natural FXR agonist.