1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEAnacetrapibCat. No.: HY-12090CAS No.: 875446-37-0Synonyms: MK-0859分式: CHFNO分量: 637.51作靶點: CETP作通路: Metabolic Enzyme/Protease儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 100 mg/mL (156.86

2、 mM)H2O : 90% corn oilSolubility: 2.75 mg/mL (4.31 mM); Clear solution1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEBIOLOGICAL ACTIVITY物活性 Anacetrapib種有效的 CETP 抑制劑，作于 rhCETP 和 C13S CETP 突變型，IC50 分別為 7.92.5 nM 和11.81.9 nM。IC50 & Target IC50: 7.92.5 nM (rhCETP), 11.81.9 nM (CETPC13S) 1體外研究 Anacetra

3、pib dose-dependently and significantly decreases the transfer of CE from HDL3 to HDL2(P14CTorcetrapib (0.25 M) binds to immobilized rhCETP by 82% and 60%, respectively. Anacetrapibdecreases pre-HDL formation by more than 46% (P 1. A significant reduction of PCSK9 promoter activityby Anacetrapib (ANA

4、) is detected at 3 M concentration (22%, p 2.體內(nèi)研究 Hamsters are given Anacetrapib for 7 days before injection of 3Hcholesterol-labeled macrophages (day 0).Treatment with Anacetrapib leads to significant increases in HDL-C levels at day 0. At day 3, 3Hcholesterolradioactivity in the HDL fraction is si

5、gnificantly increased from control values for Anacetrapib 1. Anacetrapib(ANA) treatment modestly elevates serum total serum cholesterol levels 10% (p 2. After an intravenousdose of 0.5 mg/kg, the mean values for systemic plasma clearance, steady-state volume of distribution, andterminal half-life ar

6、e 2.3 mL/min/kg, 1.1 L/kg, and 12 h, respectively. After oral dosing at 5 mg/kg, thebioavailability of Anacetrapib is 38%. Exposures (AUC) increases in a less than dose-proportional mannerfrom 23 Mh at 5 mg/kg to 362 Mh at 500 mg/kg. In this dose range, the peak plasma level (Cmax) rangesfrom 5 to 2

7、6 M and the time to reach peak plasma level (Tmax) ranged from 3 to 4.5 h 3.PROTOCOLKinase Assay 1 The inhibitory potency (IC50) of Dalcetrapib, Torcetrapib, and Anacetrapib to decrease CE transfer from HDLto LDL by rhCETP and C13S CETP is measured using a scintillation proximity assay kit. Briefly,

8、 3HCE-labeled HDL donor particles are incubated in the presence of purified CETP proteins (final concentration 0.5g/mL) and biotinylated LDL acceptor particles for 3 h at 37C. Subsequently, streptavidin-coupledpolyvinyltoluene beads containing liquid scintillation cocktail binding selectively to bio

9、tinylated LDL areadded, and the amount of 3HCE molecules transferred to LDL is measured by counting 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 2 Cells are seeded in a 96 well plate overnight prior to the treatment by different concentr

10、ations of CETPinhibitors (e.g., Anacetrapib) for 24 h. Cell viability is measured using the CellTiter-Glo Luminescent CellViability Assay kit. Four wells are evaluated under each experimental condition 2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.A

11、nimal Mice 2Administration 23 Eight-week old male C57BL/6J mice are housed (4 animals/cage) under controlled temperature (72F) andlighting (12 h light/dark cycle). Animals have free access to autoclaved water and food. In the first in vivostudy, after an acclimatization period of 7 days, mice are fe

12、d 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 groupreceive vehicle (0.5% methyl cellulose). The drug

13、 treatment lasts 7 days. In the second in vivo study, mice2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEfed a normal chow diet are treated with Anacetrapib (50 mg/kg, n=8) or vehicle (n=8) for 10 days. Serumsamples are collected after a 4 h fasting before and after the drug treatment. After the l

14、ast dosing, all animalsare sacrificed for collection of serum and liver tissues. Livers are immediately removed, cut into small pieces,and stored at 80C for RNA and protein isolations and cholesterol measurement.Rats 3Adult male Sprague-Dawley rats, weighing 280 to 330 g, are fasted overnight before

15、 the study. The animalsare 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 catheterpreviously implanted into the femoral vein, followed by a 300

16、L saline flush. The intravenous dose ofAnacetrapib is formulated in polyethylene glycol 300-water (7:3, v/v) at a concentration of 0.2 mg/mL. Fororal administration, four rats received a dose via oral gavage (dosing volume 2 mL/kg). These oral doses of5, 50, 100, and 500 mg/kg are formulated in Imwi

17、tor 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 thefollowing 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

18、, and plasma is prepared by centrifugation. Plasma is transferred to a 96-wellplate and stored at 70C until analysis.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻 Diabetes. 2018 Dec;67(12):2494-2506. PLoS One. 2017 Aug 2;12(8):e0180772.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Niesor EJ, et al. Modulating cholesteryl ester transfer protein activity maintains efficient pre-HDL formation and increases reversecholesterol transport. J Lipid Res. 201