Cholesterol ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that has been identified as a promising target for increasing circulating HDL cholesterols. Anacetrapib is an inhibitor of CETP transfer activity, which blocks CETP-dependent transfer of cholesterol esters (CE) with an IC50 value of 17 nM and of triglycerides with an IC50 of 15 nM. When testing the effect of anacetrapib on CE transfer in 95% human serum, the IC50 value was 45 nM when the preincubation time was one hour, and was 18 nM with 24-hour preincubation. Anacetrapib significantly reduced the transfer of CE form HDL3 to HDL2 at a dose-dependent manner from 0.1 to 10 μM in vitro. By adding 25 µM anacetrapib, the amount of [14C]torcetrapib (0.25 µM) bound to immobilized recombinant human CETP was significantly decreased by 60%. In human plasma with endogenous CETP level at 1.25 μg/ml, incubation of anacetrapib at 0.1, 1, 3, or 10 μM for 21 hours decreased the formation of pre-β—HDL by more than 46%. Hamsters treated with 30 mg/kg anacetrapib once daily for 7 days followed by the injection with [3H]cholesterol-labeled autologous macrophages (Day 0) showed significantly increased level of HDL cholesterol at Day 0, and elevated [3H]cholesterol radioactivity in the HDL fraction at Day 3.
作用机制
Anacetrapib inhibits CETP-mediated cholesterol ester and triglyceride transfer by competing with other ligands to reversibly bind to CETP.
Anacetrapib/安塞曲匹 细胞实验
Cell Line
Concentration
Treated Time
Description
References
THP1 cells
1 μM
CETP inhibitor increased COX-2 and caspase-1 expression and ROS activity
JCI Insight. 2024 Apr 22;9(8):e173205.
Peripheral blood mononuclear cells (PBMCs)
4 μM
CETP inhibitor dose-dependently increased COX-2 and caspase-1 expression
JCI Insight. 2024 Apr 22;9(8):e173205.
Rat adrenocortical cells
0.1–10 μM
2 hours
To evaluate the effect of Anacetrapib on aldosterone release, results showed no significant effect at concentrations up to 10 μM.
Single dose, 30 min infusion (mice, rats, dogs), single oral dose (rhesus monkeys)
To evaluate the effect of Anacetrapib on blood pressure, results showed no increase in blood pressure in all tested species.
Br J Pharmacol. 2008 Aug;154(7):1465-73.
Syrian golden hamsters
High-fat diet-induced dyslipidemic model
Dietary admix
60 mg/kg/day
Once daily for 2 weeks
To evaluate the effects of ANA on reverse cholesterol transport and cholesterol excretion, results showed that ANA significantly increased HDL-C levels, promoted macrophage-to-feces cholesterol transport, and increased fecal cholesterol and bile acid excretion.
J Lipid Res. 2011 Nov;52(11):1965-73
APOE*3-Leiden.CETP mice
Hypercholesterolemia model
Dietary supplementation
30 mg/kg body weight per day
Once daily for 21 weeks
To investigate the effects of anacetrapib on atherosclerosis, it was found that anacetrapib attenuated atherosclerosis development by reducing (V)LDL-C rather than by raising HDL cholesterol.
J Lipid Res. 2015 Nov;56(11):2085-93
APOE*3Leiden.CETP transgenic mice
Atherosclerosis model induced by cholesterol-rich diet
Dietary administration
0.03; 0.3; 3; 30 mg/kg/day
Daily administration for 21 weeks
To evaluate the effects of Anacetrapib on atherosclerosis progression and plaque stability, results showed that Anacetrapib dose-dependently reduced atherosclerotic lesion area and severity, and increased plaque stability
Eur Heart J. 2015 Jan 1;36(1):39-48
CETP transgenic mice
High-fat diet-induced obesity model
Intravenous injection
0.2 mg/mL, 2.5 mL/kg per dose
Every 12 hours, total five doses
To evaluate the effects of anacetrapib on HDL function and metabolism, results showed that anacetrapib increased HDL cholesterol levels but led to liver triglyceride accumulation and insulin resistance in HFD-fed mice
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