A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo

被引：15

作者：

Suchowerska, Alexandra K. ^{[1
]}

Stokman, Geurt ^{[2
]}

Palmer, James T. ^{[3
]}

Coghlan, Phillip A. ^{[4
]}

Pieterman, Elsbet J. ^{[2
]}

Keijzer, Nanda ^{[1
,2
]}

Lambert, Gilles ^{[5
]}

Chemello, Kevin ^{[5
]}

Jaafar, Ali K. ^{[5
]}

Parmar, Jasneet ^{[1
]}

Yan, Liping ^{[6
]}

Tong, Yingtao ^{[6
]}

Mu, Lin ^{[6
]}

Princen, Hans M. G. ^{[2
]}

Bonnar, James ^{[1
]}

Evison, Benny J. ^{[1
]}

机构：

[1] Nyrada Inc, Gordon, NSW, Australia

[2] Netherlands Org Appl Sci Res, Metab Hlth Res, Leiden, Netherlands

[3] Pharmaceut Discovery Consultat, Warrandyte, VIC, Australia

[4] i Chem Consulting, Condell Pk, NSW, Australia

[5] Univ Reunion Plateforme CYROI, Lab Inserm UMR DeTROI 1188, Sainte Clotilde, France

[6] Shanghai Chem Partner Co Ltd, Exploratory Toxicol Dept, DMPK, Shanghai, Peoples R China

来源：

JOURNAL OF LIPID RESEARCH | 2022年 / 63卷 / 11期

关键词：

Supplementary key words PCSK9; cardiovascular disease; hypercholesterolemia; small-molecule; lipoproteins; apolipoproteins; drug therapy; LDL; statins; lysosomal degradation; LDL-CHOLESTEROL; HDL-CHOLESTEROL; TRANSGENIC MICE; BILE-ACID; ATHEROSCLEROSIS; ATORVASTATIN; BINDING; ALIROCUMAB; EXPRESSION; EXCRETION;

D O I：

10.1016/j.jlr.2022.100293

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipo-protein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to cardiovascu-lar disease, PCSK9 has attracted intense interest as a therapeutic target. Despite this interest, an orally bioavailable small-molecule inhibitor of PCSK9 with extensive lipid-lowering activity is yet to enter the clinic. We report herein the discovery of NYX-PCSK9i, an orally bioavailable small-molecule inhibi-tor of PCSK9 with significant cholesterol-lowering activity in hyperlipidemic APOE*3-Leiden.CETP mice. NYX-PCSK9i emerged from a medicinal chem-istry campaign demonstrating potent disruption of the PCSK9-LDLR interaction in vitro and functional protection of the LDLR of human lymphocytes from PCSK9-directed degradation ex vivo. APOE*3-Leiden.CETP mice orally treated with NYX-PCSK9i demonstrated a dose-dependent decrease in plasma total cholesterol of up to 57%, while its combination with atorvastatin additively suppressed plasma total cholesterol levels. Importantly, the majority of cholesterol lowering by NYX-PCSK9i was in non-HDL fractions. A concomitant increase in total plasma PCSK9 levels and significant increase in hepatic LDLR protein expression strongly indicated on-target function by NYX-PCSK9i. Determinations of hepatic lipid and fecal cholesterol content demonstrated depletion of liver cholesteryl esters and promotion of fecal cholesterol elimination with NYX-PCSK9i treatment. All measured in vivo biomarkers of health indicate that NYX-PCSK9i has a good safety profile. NYX-PCSK9i is a potential new therapy for hypercholesterolemia with the capacity to further enhance the lipid-lowering activities of statins.

引用

页数：14

共 64 条

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