【摘要】 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(0.1⁰.3μmol·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。更多还原

【Abstract】 11β-HSD1 inhibitors have been viewed as a potential way for the treatment of diabetes and other elements of the metabolic syndrome due to its attractive mechanism. Based on the leading compounds 3 and 4 found in our previous study,nineteen novel amantadine derivatives containing piperazine ureas scaffold were designed and synthesized from benzylpiperazine via nitrosylation, reduction,condensation,debenylation and substitution. The compounds were evaluated by in vitro human enzyme assays. The potent compounds showed strong affinity towards 11β-HSD1 and good selectivity to 11β-HSD2. The structure-activity relationships study revealed that the aryl group length, lipophilicity and substituents play a key role for inhibition activity.Compounds 12 j, 12 m, 12 o and 12 q exhibited strong inhibitory activity against 11β-HSD1 with IC₅₀ of 0. 1-0. 3 μmol·L^-1. The most active compound 12 q( IC₅₀ = 0. 176 μmol·L^-1) was 10-fold more active than glycyrrhetinic acid( IC50 = 1. 05 μmol·L^-1). Further in vivo assays led to identification of 12 q,which substantially reduced cortisol level in mice plasma 54%. These initial biological results suggested that piperazine ureas are potential as 11β-HSD1 inhibitors for further investigation.更多还原