Title
A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo
Author
Suchowerska, A.K.
Stokman, G.
Palmer, J.T.
Coghlan, P.A.
Pieterman, E.J.
Keijzer, N.
Lambert, G.
Chemello, K.
Jaafar, A.K.
Parmar, J.
Yan, L.
Tong, Y.
Mu, L.
Princen, H.M.G.
Bonnar, J.
Evison, B.J.
Publication year
2022
Abstract
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (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 cardiovascular 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 inhibitor of PCSK9 with significant cholesterol-lowering activity in hyperlipidemic APOE∗3-Leiden.CETP mice. NYX-PCSK9i emerged from a medicinal chemistry 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. Chemicals / CAS atorvastatin, 134523-00-5, 134523-03-8, 110862-48-1; proprotein convertase 9; serine protease HTRA1; serine proteinase; cholesterol, 57-88-5; Apolipoproteins E; Cholesterol; Cholesterol, LDL; PCSK9 protein, human; Pcsk9 protein, mouse; Proprotein Convertase 9; Receptors, LDL.
Subject
apolipoproteins
cardiovascular disease
drug therapy
hypercholesterolemia
LDL
lipoproteins
lysosomal degradation
PCSK9
small-molecule
statins
atorvastatin
cholesterol ester
low density lipoprotein receptor
PCSK9 inhibitor
proprotein convertase 9
unclassified drug
[3 [[3 amino 1 piperidyl]methyl 5 (4 methyl 1h imidazole 1 yl)phenylamino](4 phenyl 2 pyridyl)formaldehyde]
apolipoprotein E
cholesterol
low density lipoprotein cholesterol
low density lipoprotein receptor
PCSK9 protein, human
Pcsk9 protein, mouse
proprotein convertase 9
animal experiment
animal model
area under the curve
blood sampling
cholesterol blood level
cohort analysis
controlled study
drug bioavailability
drug design
drug potentiation
drug safety
drug screening
drug structure
ex vivo study
female
gene expression
human
human cell
hypercholesterolemia
hyperlipidemia
hypolipidemic activity
in vitro study
in vivo study
lipid liver level
lymphocyte
male
mean residence time
medicinal chemistry
mouse
nonhuman
protein degradation
protein depletion
protein expression
single drug dose
animal
genetics
metabolism
Animals
Apolipoproteins E
Cholesterol
Cholesterol, LDL
Humans
Mice
Proprotein Convertase 9
Receptors, LDL
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DOI
https://doi.org/10.1016/j.jlr.2022.100293
TNO identifier
980052
ISSN
0022-2275
Source
Journal of Lipid Research, 63 (63)
Document type
article