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Small molecules as inhibitors of PCSK9: current status and future challenges

Xu, Shengtao; Luo, Shanshan; Zhu, Zheying; Xu, Jinyi

Small molecules as inhibitors of PCSK9: current status and future challenges Thumbnail


Shengtao Xu

Shanshan Luo

Associate Professor in International Pharmacy and Traditional Medicines

Jinyi Xu


Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed.

Journal Article Type Article
Acceptance Date Nov 5, 2018
Online Publication Date Nov 11, 2018
Publication Date 2019-01
Deposit Date Dec 5, 2018
Publicly Available Date Nov 12, 2019
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Electronic ISSN 1768-3254
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 162
Pages 212-233
Keywords PCSK9 protein; Inhibitor; Small-molecule; LDL-C; Hypercholesterolemia; Natural products; Patent
Public URL
Publisher URL
Additional Information This article is maintained by: Elsevier; Article Title: Small molecules as inhibitors of PCSK9: Current status and future challenges; Journal Title: European Journal of Medicinal Chemistry; CrossRef DOI link to publisher maintained version:; Content Type: article; Copyright: © 2018 Elsevier Masson SAS. All rights reserved.


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