Discovery of 2,3'-diindolylmethanes as a novel class of PCSK9 modulators

  • Bioorg Med Chem Lett. 2019 Aug 15;29(16):2345-2348. doi: 10.1016/j.bmcl.2019.06.014.
Gabrielle N Winston-McPherson  1 ,  Haibo Xie  1 ,  Ka Yang  1 ,  Xiaoxun Li  1 ,  Dongxu Shu  2 ,  Weiping Tang  3
Affiliations
  • 1. School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, United States.
  • 2. School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, United States; Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, United States.
  • 3. School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, United States; Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, United States. Electronic address: [email protected].
PMID: 31227343 DOI: 10.1016/j.bmcl.2019.06.014
Abstract

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 µM.

Keywords
Diindolylmethane; Hypercholesterolemia; Indole; LDLR; PCSK9.