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. 1993 Apr;82(4):408-15. doi: 10.1002/jps.2600820415.
A series of 4-substituted 1-acyl-1,2,4-triazolidine-3,5-diones demonstrated potent activity in CF1 mice when administered intraperitoneally at 20 mg/kg/day, lowering both serum cholesterol and triglyceride levels significantly. The 4-(4-chlorophenyl)-substituted compounds demonstrated better hypolipidemic activity in rodents than 4-methoxy-, 4-nitro-, and 4-t-butylphenyl substitutions. Aryl and alkyl substitutions rather than benzoyl substitutions at position 4 demonstrated good hypocholesterolemic activity. Selected compounds were examined for the mode of action in rats in which serum cholesterol and triglyceride levels were reduced after administration of 20 mg/kg/day orally; tissue lipids were reduced after 14 days of administration, and bile and fecal lipids were increased by 44-250%. Serum lipoprotein levels were also modulated by the agents, with cholesterol levels in very low density lipoprotein and low density lipoprotein fractions being reduced by 2-57%. Cholesterol levels in the high density lipoprotein fraction were elevated by 94-341%. Activities of mouse hepatic enzymes were suppressed by the agents in a manner that suggested that the compounds interfere with de novo synthesis of lipids.
一系列4-取代的1-酰基-1,2,4-三唑烷-3,5-二酮以20毫克/千克/天的剂量腹腔注射给CF1小鼠时显示出强效活性，显著降低血清胆固醇和甘油三酯水平。4-(4-氯苯基)取代的化合物在啮齿动物中显示出比4-甲氧基、4-硝基和4-叔丁基苯基取代更好的降血脂活性。4位的芳基和烷基取代而非苯甲酰基取代显示出良好的降胆固醇活性。对选定的化合物进行了大鼠作用方式的研究，口服20毫克/千克/天后血清胆固醇和甘油三酯水平降低；给药14天后组织脂质减少，胆汁和粪便脂质增加44%-250%。这些药物还调节血清脂蛋白水平，极低密度脂蛋白和低密度脂蛋白组分中的胆固醇水平降低2%-57%。高密度脂蛋白组分中的胆固醇水平升高94%-341%。这些药物以表明化合物干扰脂质从头合成的方式抑制小鼠肝酶的活性。
