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目的设计合成哌嗪脲类化合物,以期寻找具有较好体外11β-羟基类固醇脱氢酶1(11β-HSD1)选择性抑制剂。方法以2-氨基金刚烷胺和苄基哌嗪为主要起始原料,经亚硝基化、还原、缩合、脱苄基和取代反应合成目标化合物;采用均相时间分辨荧光法测试目标化合物体外对11β-HSD1的抑制活性;对优选化合物进行体外11β-HSD2筛选试验,评价化合物的特异选择性。并测定了优选化合物在小鼠体内的降皮质醇能力。结果与结论合成19个未见文献报道的哌嗪脲类化合物,其结构经~1H-NMR和MS谱确证;体外抑酶活性实验表明,部分化合物具有较好的11β-HSD1抑制作用(0.1~0.3μmol·L~(-1)),且均具有良好的选择性抑制作用;体内生物活性试验显示化合物12a和12q具有显著降低小鼠血浆皮质醇的作用(分别降低41%和54%),合成的哌嗪脲类化合物具有进一步研究的价值。
OBJECTIVE To design and synthesize piperazinyl ureas in order to find a selective 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) selective inhibitor in vitro. Methods The target compounds were synthesized from 2-aminoadamantanamine and benzylpiperazine by nitrosylation, reduction, condensation, debenzylation and substitution reactions. The target compounds were tested in vitro by homogeneous time-resolved fluorescence Inhibitory activity against 11β-HSD1; in vitro 11β-HSD2 screening of preferred compounds to evaluate the specific selectivity of the compounds. The cortisol-lowering ability of the preferred compounds in mice was determined. RESULTS AND CONCLUSIONS Nineteen piperazine ureas which were not reported in the literature were synthesized and their structures were confirmed by ~ 1H-NMR and MS spectra. The in vitro inhibition experiments showed that some compounds had good inhibitory effect on 11β-HSD1 (0.1 ~ 0.3μmol·L -1), and all had good selective inhibition. In vivo bioassay showed that compounds 12a and 12q significantly reduced the plasma cortisol level in mice (41% and 54%, respectively) Synthetic piperazine urea compounds have further research value.