Hypolipidemic arylthioalkanoic acids.
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.
D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis; D002784:Cholesterol / Q000097:blood; D000960:Hypolipidemic Agents / Q000138:chemical synthesis*; D008099:Liver / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis; D014280:Triglycerides / Q000097:blood
D002264:Carboxylic Acids; D000960:Hypolipidemic Agents; D013440:Sulfides; D014280:Triglycerides; D002784:Cholesterol