Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 29, Issue 16, Pages 2345-2348Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2019.06.014
Keywords
PCSK9; LDLR; Hypercholesterolemia; Diindolylmethane; Indole
Categories
Funding
- NIH [R01GM120357]
- Wisconsin Alumni Research Foundation (WARF)
- UW School of Pharmacy
- WARF
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM120357] Funding Source: NIH RePORTER
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low density lipoprotein receptor (LDLR). Anti-PCSK9 agents have been approved for the treatment of hypercholesterolemia. We recently discovered a series of small-molecule PCSK9 modulators that contains a relatively small pharmacophore of 2,3'-diindolylmethane with molecular weights around only 250. These molecules can significantly lower the amount of PCSK9 protein in a cell-based phenotypic assay. Our SAR studies yielded compound 16 with a IC50-value of 200 nM. No obvious cytotoxicity was observed at concentrations below 50 mu M.
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