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根据药物设计基本原理,以噻唑烷-2,4-二酮为基本结构单元设计合成了目标分子TM1~TM3系列.通过体外过氧化物酶体增殖物激活受体反应元件(PPRE)活性测定,筛选出4个PPRE相对激动活性分别为105.76%、118.15%、125.3%和100.53%的分子IM2、IM3、TM2c和TM3c(参考药物吡格列酮,100%);进一步,设计合成了IM2与IM3的衍生物TM4与TM5系列,发现了16个PPRE相对激动活性高于100%的TM4系列分子,其中TM4i和TM4y的PPRE活性最高,分别为239.77%和204.70%.毒性预测显示,高活性分子毒性较小.本研究发现了潜在的过氧化物酶体增殖物激活受体(PPAR)先导分子,为糖尿病药物的研究提供了新的思路.
According to the basic principles of drug design, the target molecules TM1 ~ TM3 series were designed and synthesized with thiazolidine-2,4-dione as the basic structural unit.According to the activity of peroxisome proliferator-activated receptor reaction element (PPRE) Four molecules of PPRE with relative agonistic activity of 105.76%, 118.15%, 125.3% and 100.53% were screened for IM2, IM3, TM2c and TM3c respectively (reference drug pioglitazone, 100%). Furthermore, derivatives of IM2 and IM3 TM4 and TM5 series and found 16 TM4 series molecules with relative PPRE of more than 100%, of which TM4i and TM4y have the highest PPRE activity of 239.77% and 204.70%, respectively. Toxicity prediction shows that high activity molecules are less toxic. This study found that the potential peroxisome proliferator-activated receptor (PPAR) lead molecule provides a new idea for the study of diabetes drugs.