Discovery of (2‐(4‐Substituted phenyl)quinolin‐4‐yl)(4‐isopropylpiperazin‐1‐yl)methanone Derivatives as Potent Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors

Abstract Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an increasingly important role in the treatment of hyperlipidemia. In pursuit of potent small molecules that block the PCSK9/low‐density lipoprotein receptor (LDLR) protein−protein interaction (PPI), a series of 2‐phenylquinoline‐4‐carboxylic acid derivatives were designed and synthesized based on previously derived molecules. In the in vitro PPI inhibition test, compounds M1 , M12 , M14 , M18 and M27 exhibited potent activities with IC 50 values of 6.25 μM, 0.91 μM, 2.81 μM, 4.26 μM and 0.76 μM, respectively, compared with SBC‐115337 (IC 50 value of 9.24 μM). Molecular docking and molecular dynamics simulations revealed the importance of hydrophobic interactions in the binding of inhibitors to the PPI interface of PCSK9. In LDLR expression and LDL uptake assays, the tested compounds M1 , M12 and M14 were found to restore LDLR expression levels and to increase the extracellular LDL uptake capacity of HepG2 cells in the presence of exogenous PCSK9. Collectively, novel small‐molecule PCSK9/LDLR PPI inhibitors (especially M12 ) with in vitro lipid lowering ability, were discovered as lead compounds for further development of hypolipidemic drugs.