Discovery and SAR analysis of phenylbenzo[d][1,3]dioxole-based proprotein convertase subtilisin/kexin type 9 inhibitors |
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| Authors: | Fahui Li Lihui Zhang Jinhong Feng Lei Zhang |
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| Affiliation: | aDepartment of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, China;bSchool of Stomatology, Weifang Medical University, Weifang, China;cShandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China |
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| Abstract: | Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapeutic target for the development of cholesterol-lowering drugs. In the discovery of PCSK9/LDLR (low-density lipoprotein receptor) protein-protein interaction (PPI) impairing small molecules, a total of 47 phenylbenzo[d][1,3] dioxole-based compounds were designed and synthesised. The result revealed that the 4-chlorobenzyl substitution in the amino group is important for the PPI disrupting activity. In the hepatocyte-based functional tests, active compounds such as A12, B1, B3, B4 and B14, restored the LDLR levels on the surface of hepatic HepG2 cells and increased extracellular LDL uptake in the presence of PCSK9. It is notable that molecule B14 exhibited good performance in all the evaluations. Collectively, novel structures targeting PCSK9/LDLR PPI have been developed with hypolipidemic potential. Further structural modification of derived active compounds is promising in the discovery of lead compounds with improved activity for the treatment of hyperlipidaemia-related disorders. |
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| Keywords: | PCSK9 LDLR protein-protein interaction LDL small molecule |
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