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

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.

Atherosclerosis; Cholesterol; PCSK9; Structure–activity relationship; Transcriptional inhibition.