Structure-activity relationship and biological evaluation of xanthine derivatives as PCSK9 inhibitors for the treatment of atherosclerosis

• Published in: European journal of medicinal chemistry 2023-02, Vol.247, p.115047, Article 115047
• Main Authors: Qiao, Meng-Qian, Li, Yue, Yang, Yu-Xin, Pang, Chen-Xu, Liu, Yi-Ting, Bian, Cong, Wang, Li, Chen, Xiao-Fang, Hong, Bin
• Format: Article
• Language: English
• Subjects: Alkaloids - therapeutic use; Animals; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Cholesterol; Mice; PCSK9; PCSK9 Inhibitors; Proprotein Convertase 9 - metabolism; Receptors, LDL - metabolism; Receptors, LDL - therapeutic use; Structure-Activity Relationship; Transcriptional inhibition; Xanthines
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.115047

Developing non-statin small molecules for the treatment of hypercholesterolemia remains challenging. The proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted therapies have attracted considerable attentions. Forty-five 7030B-C5 derivatives were synthesized and evaluated for the PCSK9 repression activity, taking the PCSK9 transcriptional inhibitor 7030B-C5 as the lead. Structure-activity relationship (SAR) analysis at C8 and N7-position was carried out, and compound 3s and 5r exhibited comparable PCSK9 transcriptional inhibitory activity but much lower cytotoxicity with the therapeutic index (TI) values doubled of that of 7030B-C5. In the in vitro assay, both compounds significantly reduced the level of PCSK9 protein and increased LDL receptor (LDLR) protein level. What's more, both compounds promoted LDL cholesterol (LDL-C) clearance more efficiently than 7030B-C5 in HepG2 cells. Most importantly, compound 3s reduced the atherosclerotic plaque areas with promising lipid-lowing effects in ApoE KO mice with a higher in vivo activity and lower toxicity. The regulatory mechanism of 3s was explored that it might target the transcription factor HNF1α and/or HINFP upstream of PCSK9 transcription, similar to that of 7030B-C5. Thus, 3s was considered as a potential anti-atherosclerosis drug candidate as a novel PCSK9 down-regulatory agent, worthy of further investigations. [Display omitted] •Novel PCSK9 modulators were synthesized and evaluated in vitro and in vivo.•Compound 3s promoted more LDL-C clearance than 7030B-C5 via PCSK9 in vitro.•Compound 3s exhibited much lower cytotoxicity than 7030B-C5.•Compound 3s reduced TC and plaque with higher in vivo activity and lower toxicity.•Compound 3s could be a potential candidate for the treatment of hyperlipidemia.