Xu Xianxiu, Fu Renzhong, Chen Jin, Chen Shengwu, Bai Xu
The Center for Combinatorial Chemistry and Drug Discovery, Jilin University, 75 Haiwai Street, Changchun, Jilin 130012, PR China.
Bioorg Med Chem Lett. 2007 Jan 1;17(1):101-4. doi: 10.1016/j.bmcl.2006.09.078. Epub 2006 Sep 30.
The underlying principle of drug design in this paper is that the maximum retention of the functional groups that exist in the marketed drug would provide a higher probability for comparable safety while the conformational changes in the newly created analogs should not constitute a significant structural variation to adversely affect biological activity. Four individual isomers of backbone re-organized ezetimibe analogs were designed and synthesized. Their effects on the cholesterol levels in rat serum were evaluated by a high-cholesterol and high-fat diet feeding experiment. All the new analogs showed significant effect in lowering the levels of total cholesterol in serum.
本文中药物设计的基本原理是，市售药物中存在的官能团最大程度保留将为可比的安全性提供更高的概率，而新合成类似物中的构象变化不应构成显著的结构变异以对生物活性产生不利影响。设计并合成了骨架重新组织的依泽替米贝类似物的四种单一异构体。通过高胆固醇和高脂肪饮食喂养实验评估了它们对大鼠血清中胆固醇水平的影响。所有新类似物在降低血清总胆固醇水平方面均显示出显著效果。
