8-SUBSTITUTED PURINE DERIVATIVES - A NEW CLASS OF LIPID-LOWERING AGENTS

A series of purine derivatives have been prepared and their in vivo abilities to lower plasma total cholesterol and triglyceride levels, and to elevate high density lipoprotein (HDL) cholesterol levels in hyperlipemic rats have been tested. Some compounds, among which 8-{2-(R)-hydroxy-3-[(p-isobutoxycarbonyl)phenoxy]propylthio}adenosine 31, 8-{3-[(p-isobutoxy carbonyl)phenoxy]-2-oxopropylthio} adenosine 33 and 8-{3-[(p-isobutoxycarbonyl)phenoxy]-2-hydrazonecarboxamidepropylthio} adenosine 36 appear to be the most interesting, have been found to have both the desired profile of activity and no hepatotoxicity, when administered po at 50, 100 or 300 mg/kg. Compounds 31, 33 and 36, orally tested at the same doses in the 15-d test, lower triglyceride and VLDL/LDL (very low density lipoprotein/low density lipoprotein) cholesterol levels by 10-33% and 13-46%, respectively, and increase HDL-associated cholesterol levels by 10-32%. These molecules have been chosen for further pharmacological and toxicological evaluations.