Patent Evaluation: Novel Dioxolanes as Cholesterol Lowering Agents

Summary

Novelty: Novel 1,3-dioxolane derivatives are disclosed and are claimed to be inhibitors of the cytochrome P-450 enzyme lanosterol 14α-demethylase. They are said to be less effective at inhibiting other cytochrome P-450 enzymes, in particular those which contribute to gonadal and adrenal steroidogenesis and cholesterol degradation; hence they may have utility in treating disease states characterized by hypercholesterolaemia.

Biology: The ability of the compounds to inhibit intracellular cholesterol synthesis was tested using human skin fibroblasts by a modification of the method of Kraemer et al. The IC₅₀ values of the free base and dihydrochloride salt of a compound were found to be 0.09nM and 0.2nM, respectively. Both were found to be more effective than ketocenazole (IC₅₀ = 48nM) at inhibiting cholesterol synthesis (demethylation step).

Chemistry: Thirteen compounds are exemplified by synthesis, which was by standard techniques. (2S,4S)-Cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-amino phenyl-thio)methyl-1,3-dioxolane is a specifically claimed compound.