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: weiping.tang@wisc.edu.

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.

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