Simlot R, Izydore R A, Wong O T, Hall I H
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
J Pharm Sci. 1994 Mar;83(3):367-71. doi: 10.1002/jps.2600830320.
A series of 4-substituted 1,2-diacyl-1,2,4-triazolidine-3,5-diones were synthesized and shown to be hypolipidemic in rodents; serum cholesterol and triglyceride levels were significantly reduced following intraperitoneal and oral dosing at 20 mg/kg/day. The hypolipidemic activity of the triazolidine-3,5-diones was improved when R1 was either a phenyl or a butyl group. Tissue lipid levels were reduced in the liver, aorta, and small intestine, while fecal lipids, e.g. cholesterol, were increased after 14 days. Very low density lipid cholesterol levels were reduced but high density lipid cholesterol levels were significantly increased. It appears that the mode of action of the 1,2-diacyl-1,2,4-triazolidine-3,5-diones is by the inhibition of the de novo rate limiting enzyme for lipid synthesis. Enzyme activities suppressed by the agents included ATP-dependent citrate lyase, HMG CoA reductase, acyl CoA cholesterol acyl transferase, acetyl CoA carboxylase, sn-glycerol-3-phosphate aryl transferase, phosphatidylate phosphohydrolase, and cholesterol-7 alpha-hydroxylase.
合成了一系列4-取代的1,2-二酰基-1,2,4-三唑烷-3,5-二酮，结果表明这些化合物在啮齿动物中具有降血脂作用；以20mg/kg/天的剂量进行腹腔注射和口服给药后，血清胆固醇和甘油三酯水平显著降低。当R1为苯基或丁基时，三唑烷-3,5-二酮的降血脂活性得到改善。给药14天后，肝脏、主动脉和小肠中的组织脂质水平降低，而粪便脂质（如胆固醇）增加。极低密度脂蛋白胆固醇水平降低，但高密度脂蛋白胆固醇水平显著升高。1,2-二酰基-1,2,4-三唑烷-3,5-二酮的作用方式似乎是通过抑制脂质合成的从头速率限制酶。这些药物抑制的酶活性包括ATP依赖性柠檬酸裂解酶、HMG CoA还原酶、酰基辅酶A胆固醇酰基转移酶、乙酰辅酶A羧化酶、sn-甘油-3-磷酸芳基转移酶、磷脂酸磷酸水解酶和胆固醇-7α-羟化酶。
