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Anacetrapib (MK-0859)

RhCETP/mutant CETP(C13S) inhibitor CAS# 875446-37-0

Anacetrapib (MK-0859)

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Chemical structure

Anacetrapib (MK-0859)

3D structure

Chemical Properties of Anacetrapib (MK-0859)

Cas No. 875446-37-0 SDF Download SDF
PubChem ID 11556427 Appearance Powder
Formula C30H25F10NO3 M.Wt 637.51
Type of Compound N/A Storage Desiccate at -20°C
Synonyms MK-0859
Solubility DMSO : ≥ 100 mg/mL (156.86 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[[2-(4-fluoro-2-methoxy-5-propan-2-ylphenyl)-5-(trifluoromethyl)phenyl]methyl]-4-methyl-1,3-oxazolidin-2-one
SMILES CC1C(OC(=O)N1CC2=C(C=CC(=C2)C(F)(F)F)C3=CC(=C(C=C3OC)F)C(C)C)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F
Standard InChIKey MZZLGJHLQGUVPN-HAWMADMCSA-N
Standard InChI InChI=1S/C30H25F10NO3/c1-14(2)22-11-23(25(43-4)12-24(22)31)21-6-5-18(28(32,33)34)9-17(21)13-41-15(3)26(44-27(41)42)16-7-19(29(35,36)37)10-20(8-16)30(38,39)40/h5-12,14-15,26H,13H2,1-4H3/t15-,26-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Anacetrapib (MK-0859)

DescriptionAnacetrapib is a potent, selective, reversible inhibitor of rhCETP and mutant CETP(C13S) with IC50 values of 7.9 nM and 11.8 nM, respectively.
TargetsrhCETPmutant CETP(C13S)    
IC507.9 nM11.8 nM    

Protocol

Kinase Assay [1]
The inhibitory potency (IC50) of Dalcetrapib, Torcetrapib, and Anacetrapib to decrease CE transfer from HDL to LDL by rhCETP and C13S CETP is measured using a scintillation proximity assay kit. Briefly, [3H]CE-labeled HDL donor particles are incubated in the presence of purified CETP proteins (final concentration 0.5 µg/mL) and biotinylated LDL acceptor particles for 3 h at 37°C. Subsequently, streptavidin-coupled polyvinyltoluene beads containing liquid scintillation cocktail binding selectively to biotinylated LDL are added, and the amount of [3H]CE molecules transferred to LDL is measured by β counting[1].

Cell Assay [2]
Cells are seeded in a 96 well plate overnight prior to the treatment by different concentrations of CETP inhibitors (e.g., Anacetrapib) for 24 h. Cell viability is measured using the CellTiter-Glo Luminescent Cell Viability Assay kit. Four wells are evaluated under each experimental condition[2].

Animal Administration [2][3]
Mice[2] Eight-week old male C57BL/6J mice are housed (4 animals/cage) under controlled temperature (72°F) and lighting (12 h light/dark cycle). Animals have free access to autoclaved water and food. In the first in vivo study, after an acclimatization period of 7 days, mice are fed a high-fat high-cholesterol diet (HFHC) containing 35% calories from fat and 1.25% cholesterol for two weeks. Mice are then divided into two groups (n=8 per group) and are given a daily dose of Anacetrapib at 50 mg/kg by oral gavage. The control group receive vehicle (0.5% methyl cellulose). The drug treatment lasts 7 days. In the second in vivo study, mice fed a normal chow diet are treated with Anacetrapib (50 mg/kg, n=8) or vehicle (n=8) for 10 days. Serum samples are collected after a 4 h fasting before and after the drug treatment. After the last dosing, all animals are sacrificed for collection of serum and liver tissues. Livers are immediately removed, cut into small pieces, and stored at −80°C for RNA and protein isolations and cholesterol measurement. Rats[3] Adult male Sprague-Dawley rats, weighing 280 to 330 g, are fasted overnight before the study. The animals are allowed access to food 4 h after dosing, but water is provided ad libitum. For intravenous administration, four rats received a dose of Anacetrapib (dosing volume 2.5 mL/kg) via bolus injection through a catheter previously implanted into the femoral vein, followed by a 300 μL saline flush. The intravenous dose of Anacetrapib is formulated in polyethylene glycol 300-water (7:3, v/v) at a concentration of 0.2 mg/mL. For oral administration, four rats received a dose via oral gavage (dosing volume 2 mL/kg). These oral doses of 5, 50, 100, and 500 mg/kg are formulated in Imwitor 742-Tween 80 (1:1, w/w) at concentrations of 2.5, 25, 50, and 250 mg/mL, respectively. Blood samples (0.3 mL) are collected into EDTA-containing tubes at the following time points: predose and 0.083 (intravenous only), 0.25, 0.5, 1, 2, 4, 6, 8, 24, and 48 h postdose. Blood samples are stored on ice, and plasma is prepared by centrifugation. Plasma is transferred to a 96-well plate and stored at −70°C until analysis.

References:
[1]. Niesor EJ, et al. Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport. J Lipid Res. 2010, 51(12), 3443-3454. [2]. Dong B, et al. CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo through a SREBP2 dependent mechanism. Atherosclerosis. 2014 Aug;235(2):449-62. [3]. Tan EY, et al. Pharmacokinetics, metabolism, and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in rats and rhesus monkeys. Drug Metab Dispos. 2010, 38(3), 459-473.

Anacetrapib (MK-0859) Dilution Calculator

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Preparing Stock Solutions of Anacetrapib (MK-0859)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.5686 mL 7.843 mL 15.686 mL 31.3721 mL 39.2151 mL
5 mM 0.3137 mL 1.5686 mL 3.1372 mL 6.2744 mL 7.843 mL
10 mM 0.1569 mL 0.7843 mL 1.5686 mL 3.1372 mL 3.9215 mL
50 mM 0.0314 mL 0.1569 mL 0.3137 mL 0.6274 mL 0.7843 mL
100 mM 0.0157 mL 0.0784 mL 0.1569 mL 0.3137 mL 0.3922 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Anacetrapib (MK-0859)

Anacetrapib, also known as MK-0859, is a potent and selective inhibitor of cholesteryl ester transfer protein (CETP) that exhibits strong inhibition against CETP-mediated transfer of cholesteryl esters and triglycerides with values of inhibition constant IC50 of 16 nM and 29 nM respectively. Anacetrapib is mainly metabolized by CYP3A4 through O-demethylation, hydroxylation on the biphenyl moiety and hydroxylation on the isopropyl side chain resulting in three oxidative metabolites M1, M2 and M3 respectively. Anacetrapib is being investigated for the treatment of primary hypercholesterolemia and mixed hyperlipidemia due to its impressive effects to lower low-density lipoprotein (LDL) cholesterol levels and increase high-density lipoprotein (HDL) cholesterol levels without any associated major adverse events.

Reference

Tan EY, Hartmann G, Chen Q, Pereira A, Bradley S, Doss G, Zhang AS, Ho JZ, Braun MP, Dean DC, Tang W, Kumar S. Pharmacokinetics, metabolism, and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in rats and rhesus monkeys. Drug Metab Dispos. 2010;38(3):459-473.

Kumar S, Tan EY, Hartmann G, Biddle Z, Bergman AJ, Dru J, Ho JZ, Jones AN, Staskiewicz SJ, Braun MP, Karanam B, Dean DC, Gendrano IN, Graves MW, Wagner JA, Krishna R. Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans. Drug Metab Dispos. 2010;38(3):474-483

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References on Anacetrapib (MK-0859)

Efficacy and safety after cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859) in patients with primary hypercholesterolemia or mixed hyperlipidemia.[Pubmed:21982664]

Am Heart J. 2011 Oct;162(4):708-16.

This report describes the lipid and safety data collected during an off-drug period that followed 8 weeks of treatment with the cholesteryl ester transfer protein inhibitor, anacetrapib (ANA). A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia were randomized to placebo, atorvastatin (ATV) 20 mg, and varying doses of ANA, provided as monotherapy or coadministered with ATV 20 mg daily. Patients were treated for 8 weeks, followed by an 8-week follow-up period, during which ANA was switched to placebo. At week 16 (8 weeks after ANA was stopped), persistent reductions in low-density lipoprotein cholesterol (LDL-C) were evident for the monotherapy groups receiving ANA 150 and 300 mg (-9.3% and -15.3%, respectively), and residual increases in high-density lipoprotein cholesterol (HDL-C) were observed for the monotherapy groups receiving ANA 40 mg (18.6%), 150 mg (40.5%), and 300 mg (43.4%). The effects on apolipoprotein B and apolipoprotein A-I were consistent with the changes observed for LDL-C and HDL-C, respectively. Corresponding residual changes in LDL-C and HDL-C were also noted in the ATV coadministration groups at the similar doses of ANA compared with ATV 20 mg alone. Residual plasma drug levels accompanied by reductions in cholesteryl ester transfer protein activity were observed at week 16 and may account for the alterations in plasma lipids 8 weeks after cessation of ANA.

Description

Anacetrapib is a potent CETP inhibitor, with IC50s of 7.9±2.5 nM and 11.8±1.9 nM for rhCETP and C13S CETP mutant, respectively.

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