New chemotype of selective and potent inhibitors of human delta 24-dehydrocholesterol reductase.
Level 5 - mechanism / opinion, no new human data
Bench and animal research (in vitro and mouse in vivo preclinical study)
PubMed 28964935 · doi:10.1016/j.ejmech.2017.08.011
What was done
Starting from the lathosterol-derived lead MGI-21, researchers systematically altered the side-chain functionality to design and synthesize new selective inhibitors of human delta 24-dehydrocholesterol reductase (DHCR24). Compounds were evaluated in vitro for potency, selectivity, and cytotoxicity using HL-60 cells, and lead diester 27 (SH-42) was administered to mice to test its ability to alter plasma desmosterol levels.
What was found
The parent compound MGI-21 inhibited overall cholesterol biosynthesis in HL-60 cells with an IC50 of 823 nM. The newly synthesized steroidal 3,22-diols (compounds 29 and 30) and several of their esters demonstrated DHCR24 inhibition with IC50 values below 5 nM while exhibiting low toxicity and high selectivity. In vivo, diester 27 (SH-42) caused a statistically significant increase in murine plasma desmosterol levels, though exact in vivo quantities and baseline-to-endpoint numbers were not reported in the abstract.
Why it matters
Selective and non-toxic DHCR24 inhibitors have potential utility as chemical probes and therapeutic candidates for conditions involving cholesterol precursor pathways, including hepatitis C virus infection, atherosclerosis, and certain cancers.
Limits
This is an early-stage preclinical study limited to cell lines and a mouse model; human pharmacokinetic and clinical safety data are absent. The abstract omits mouse sample sizes, specific dosage regimens, and exact numerical measurements for the in vivo desmosterol increase.
Cited by
- supports Triparanol, approved in the 1950s/1960s to lower cholesterol, worked by inhibiting the enzyme converting desmosterol to cholesterol, which caused desmosterol accumulation and increased heart attacks.