New chemotype of selective and potent inhibitors of human delta 24-dehydrocholesterol reductase

摘要

Abstract The enzyme Δ 24 -dehydrocholesterol reductase (DHCR24) catalyzes the reduction of the Δ 24 -double bond in the side chain of cholesterol precursors. Recent biochemical investigations fuel the hope that inhibition of DHCR24, resulting in an accumulation of desmosterol, can open new therapeutic options for treating hepatitis C virus infections, certain forms of cancer and atherosclerosis. In turn, there is a high need for selective, potent and non-toxic inhibitors of DHCR24. Previous reports as well as our re-evaluation showed that established DHCR24 inhibitors are not suitable for this purpose. Based on the lathosterol-derived amide MGI-21 (IC 50 823?nM for inhibition of overall cholesterol biosynthesis in HL-60?cells) we performed a systematic variation of the side chain functionality and identified the steroidal 3,22-diols 29 and 30 , as well as several esters thereof, as extremely potent (IC 50 ? 27 (SH-42) led to a significant increase in plasma desmosterol levels. The new inhibitors described here are valuable tools for investigating the therapeutic potential of DHCR24 inhibition. Graphical abstract Display Omitted Highlights ? New chemotype of mammalian Δ 24 -dehydrocholesterol reductase (DHCR24) inhibitors. ? Characterization of highly active, selective and non-toxic steroidal inhibitors. ? Compound 27 (SH-42) has submicromolar activity on human DHCR24. ? Significant accumulation of desmosterol in mice under SH-42 treatment after 5 days.