苯氧丁酸类非甾体5α-还原酶抑制剂的设计、合成及活性研究

Design,synthesis and biological activity assessment of phenoxybutyric acid derivatives as nonsteroidal 5α-reductase inhibitors

目的设计合成苯氧丁酸类非甾体5α-还原酶抑制剂,对其进行活性测试。方法以苯基哌嗪哒嗪酮为骨架,引入苯氧丁酸及不同的取代基,设计8个非甾体5α-还原酶抑制剂。以不同取代的苯基哌嗪为原料,与3,6-二氯哒嗪反应制备相应苯基哌嗪哒嗪酮,再与烷基链长度不同的苯氧丁酸乙酯中间体反应得目标化合物。结果所得目标化合物经1H-NMR、MS确认结构,并以非那雄胺为阳性对照药,对其进行体外活性筛选,有7个化合物具有抑制活性。结论活性测试显示7个目标化合物有一定的5α-还原酶抑制活性,其中,化合物A1和A7的抑制活性较好,在3.3×10-5mol/L水平的抑制率分别是A1(12.50%)、A7(19.64%)。

Objective To synthesize phenoxybutyric acid derivatives as 5α-reductase inhibitors and test their biological activities in vitro. Methods Eight analogues as nonsteroidal 5α-reductase inhibitors were designed and synthesized by substitution reaction of 6-（4-phenyl-piperazine-1-yl）-3（2H）-pyridazinone with phenoxybutyric acid derivatives. Results and Conclusion The structures of the compounds were characterized by 1H-NMR and MS. Biological evaluation indicated that 7 out of the 8 compounds exhibited moderate 5α-reductase inhibitory activities, especially the compounds A1 and A7 with inhibition rates reaching 12.50%and 19.64%at the concentration of 3.3×10-5 mol/L, respectively.