Wagner E R, Dull R G, Mueller L G, Allen B J, Renzi A A, Rytter D J, Barnhart J W, Byers C
J Med Chem. 1977 Aug;20(8):1007-13. doi: 10.1021/jm00218a004.
A series of arylthioalkanoic acids related to probucol was studied for hypolipidemic activity. Homologation of the alkyl side chain led to marked changes in the serum cholesterol and serum triglyceride lowering activity in rats with the best combination of properties appearing in compound 7, 2-[3,5-di-tert-butyl-4-hydroxyphenyl)thio]hexanoic acid. Modification of the ring substitution failed to improve the activity despite the empirical observation that lipophilic substitution was necessary. Removal of the phenolic hydroxyl produced compound 23 with properties similar to 7 but of somewhat lower activity. Replacement of the sulfur by oxygen increased the toxicity of the series. Resolution of racemic 7 did not change the activity of the compound. The LD50 in mice of 7 was between 5000 and 10 000 mg/kg and compound 7 has been submitted for human clinical evaluation.
研究了一系列与普罗布考相关的芳硫基链烷酸的降血脂活性。烷基侧链的同系化导致大鼠血清胆固醇和血清甘油三酯降低活性发生显著变化，化合物7（2-[3,5-二叔丁基-4-羟基苯基)硫代]己酸）表现出最佳的性能组合。尽管根据经验观察亲脂性取代是必要的，但环取代的修饰未能提高活性。去除酚羟基得到化合物23，其性质与7相似，但活性略低。用氧取代硫增加了该系列化合物的毒性。外消旋7的拆分并未改变该化合物的活性。7在小鼠中的半数致死量在5000至10000mg/kg之间，化合物7已提交人体临床评估。
