Goel R K, Thind J S, Bal C S, Mahajan M P, Kulkarni S K
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Pharmazie. 2005 May;60(5):369-74.
Some novel substituted azetidin-2-ones (5-8) were synthesized via [2 + 2] cycloaddition reactions of imines and ketenes and evaluated for their ability to prevent diet and diabetes induced hypercholesterolemia. The test compounds 5a and 7a significantly (p < 0.01) inhibited the rise in serum total cholesterol induced by peanut oil (5.5%), cholesterol (1.5%) and cholic acid (0.5%) diet in both acute and chronic models in a dose dependent manner. Compound 5a also raised the high density lipoprotein-cholesterol levels in chronic diet models by peanut oil (5.5%), cholesterol (1.5%) and cholic acid (0.5%). In a diabetes induced model of hypercholesterolemia, the test compounds were evaluated for preventing diabetes-induced hypercholesterolemia (protocol 1) as well as for lowering post diabetic hypercholesterolemia (protocol 2). Test compounds 5a-g and 7a-d significantly (p < 0.05) reduced serum total cholesterol with a greater reduction in protocol 1 as compared with protocol 2. Based on SAR studies, the substituents that favor hypocholesterolemic activity around the azetidin-2-one nucleus are discussed and a possible mechanism of action is proposed on the basis of their differential effects in two protocols of diabetes-induced hypercholesterolemia.
通过亚胺与烯酮的[2 + 2]环加成反应合成了一些新型取代的氮杂环丁烷-2-酮（5 - 8），并评估了它们预防饮食和糖尿病诱导的高胆固醇血症的能力。测试化合物5a和7a在急性和慢性模型中均以剂量依赖性方式显著（p < 0.01）抑制了由花生油（5.5%）、胆固醇（1.5%）和胆酸（0.5%）饮食诱导的血清总胆固醇升高。化合物5a在由花生油（5.5%）、胆固醇（1.5%）和胆酸（0.5%）组成的慢性饮食模型中还提高了高密度脂蛋白胆固醇水平。在糖尿病诱导的高胆固醇血症模型中，评估了测试化合物预防糖尿病诱导的高胆固醇血症（方案1）以及降低糖尿病后高胆固醇血症（方案2）的能力。测试化合物5a - g和7a - d显著（p < 0.05）降低了血清总胆固醇，与方案2相比，方案1中的降低幅度更大。基于构效关系研究，讨论了氮杂环丁烷-2-酮核周围有利于降胆固醇活性的取代基，并根据它们在糖尿病诱导的高胆固醇血症的两个方案中的不同作用提出了可能的作用机制。
