The enzyme Δ²⁴-dehydrocholesterol reductase (DHCR24) catalyzes the reduction of the Δ²⁴-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 (IC₅₀ 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 (IC₅₀ < 5 nM), selective, and non-toxic DHCR24 inhibitors. In mice, diester 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.

酶Δ ²⁴ -dehydrocholesterol还原酶（DHCR24）催化Δ的减少²⁴中胆固醇的前体的侧链-双键。最近的生化研究激发了人们的希望，即抑制DHCR24导致去氢甾醇的积累，可以为治疗丙型肝炎病毒感染，某些形式的癌症和动脉粥样硬化开辟新的治疗选择。反过来，非常需要选择性，有效和无毒的DHCR24抑制剂。先前的报道以及我们的重新评估表明，既定的DHCR24抑制剂不适合该目的。基于源自谷甾醇的酰胺MGI-21（IC ₅₀823 nM用于抑制HL-60细胞中总体胆固醇的生物合成），我们对侧链功能进行了系统的检测，并确定甾体3,22-二醇29和30以及其几种酯具有极强的效力（IC ₅₀  <5 nM），选择性且无毒的DHCR24抑制剂。在小鼠中，二酯27（SH-42）导致血浆去血甾醇水平显着增加。此处描述的新抑制剂是研究DHCR24抑制作用的潜在治疗方法的宝贵工具。