Small molecules as inhibitors of PCSK9: Current status and future challenges.

Shengtao Xu, Shanshan Luo, Zheying Zhu, Jinyi Xu

Journal: European journal of medicinal chemistry 2019;162():212-233

PMID: 30448414

Full Text on Elsevier Science View on PubMed

Abstract

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.

Address: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, PR China.; Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham, NG7 2RD, UK.; State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: [email protected].

DOI: 10.1016/j.ejmech.2018.11.011