Patent Evaluation: Novel HMG-CoA Reductase Inhibitors

Summary

Novelty: Known and previously disclosed 10-membered lactone decanolides and diploalides are disclosed and are said to exhibit an inhibitory action on HMG-CoA reductase. The compounds are potentially useful hypocholesterolaemic and anti-arterioscleroic agents.

Biology: Inhibition of HMG-CoA reductase by the compounds was demonstrated in cell cultures of HEP-G2 hepatocytes, where the preferred compound gave an IC₅₀ = 0.1 μM for cholesterol synthesis. In vivo rodent studies showed an elevation of HDL/LDL plasma lipoprotein ratio at a daily dose of 15 mg/kg po, an action comparable with the known agents lovastatin and clofibrate.

Chemistry: The ten-membered lactones were isolated from the fermentation medium of penicillium species, followed by derivatization by conventional methods as disclosed in EP0333024-A.

Structure: