Discovery of 2, 3′-diindolylmethanes as a novel class of PCSK9 modulators. Issue 16 (15th August 2019)

• Record Type: Journal Article
• Authors: Winston-McPherson, Gabrielle N.; Xie, Haibo; Yang, Ka; Li, Xiaoxun; Shu, Dongxu; Tang, Weiping
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 16(2019)
• Page Start: 2345
• Page End: 2348
• Publication Date: 2019-08-15
• Subjects: PCSK9 -- LDLR -- Hypercholesterolemia -- Diindolylmethane -- Indole; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.06.014
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.