Stereoselective synthesis of a new class of potent and selective inhibitors of human Δ8,7-sterol isomerase

Secosteroid-type cis-configured amino alcohols are potent and selective inhibitors of human Δ8,7-sterol isomerase in cholesterol biosynthesis, whereas epimeric trans-aminoalcohols and aminoketones are inactive. Starting from Grundmann′s ketone a new chemotype of inhibitors of the post-squalene part of cholesterol biosynthesis was developed. Stereoselective introduction of an angular methyl group at C-3a, followed by a plethora of functionalisations at C-4 and C-5 led to cis-configured amino alcohols as a new chemotype of inhibitors of cholesterol biosynthesis. In cell-based screening systems these compounds were identified to be selective inhibitors of human Δ8,7-sterol isomerase, inhibiting total cholesterol biosynthesis with IC50 values in the low nanomolar range. The most active compounds did not affect fungal Δ8,7-sterol isomerase (in ergosterol biosynthesis), neither showed noteworthy antimicrobial and cytotoxic effects.