Abstract
Studies described here address structure-activity relationships of novel hypolipidemic agents that induce peroxisome proliferation. Male rats were given equivalent doses of three well-studied fibrates, fibrate amides, and structurally dissimilar agents. Aryloxyalkanoic acids, amide analogs, and thio, benzimidazole, phenylpiperazine, and oxazole derivatives induced peroxisome proliferation and decreased plasma cholesterol and triglyceride levels. These compounds contain an acidic function or appear to be readily metabolized to a derivative with an acidic function. Substitution of this substituent with an adamantyloxy eliminated peroxisome proliferation and induced contrasting effects on the lipid profile, substantially increasing triglycerides. A direct correlation was established between hepatocellular peroxisome proliferation and plasma high-density lipoprotein (HDD-cholesterol levels.