Steroidomimetic Aminomethyl Spiroacetals as Novel Inhibitors of the Enzyme Δ8,7-Sterol Isomerase in Cholesterol Biosynthesis

Grundmann's ketone is converted to a spiroacetal containing a 5‐hydroxymethyl‐5‐nitro‐1,3‐dioxane moiety whose hydroxymethyl group can be esterified or directly substituted with primary and secondary amines. Among the resulting aminomethyl spiroacetals, several ones bearing diamino residues were found to be inhibitors of the enzyme Δ8,7‐isomerase in cholesterol biosynthesis. The complex bicyclic building block derived from Grundmann's ketone could be replaced by a properly substituted tetraline scaffold, without noteworthy loss in activity. This opens the opportunity to perform further structural modifications for the design of new steroidomimetic inhibitors of human Δ8,7‐isomerase. Aminomethyl spiroacetals derived from Grundmann's ketone were identified as a new chemotype of inhibitors of human Δ8,7‐sterol isomerase. In a second step, an equipotent but not cytotoxic tetraline analog was developed as potent inhibitor of cholesterol biosynthesis.