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Research Area
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Description
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Hyperlipidaemia, Hypercholesterolaemia , Atherosclerosis |
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Biological Activity
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Description
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Anacetrapib (MK0859) is a potent and selective rhCETP and mutant CETP(C13S) inhibitor with IC50 of 7.9 nM and 11.8 nM, respectively |
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Targets
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rhCETP |
Mutant CETP (C13S) |
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IC50 |
7.9 nM |
11.8 nM [1] |
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In Vitro
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Anacetrapib is not only able to increase HDL-cholesterol, but also further decreases LDL-cholesterol when taken in combination with a statin. Anacetrapib dose-dependently and significantly decreases the transfer of CE from HDL3 to HDL2. Anacetrapib doesn’t affect the amount of [14C]-dalcetrapibthiol bound to rhCETP. Anacetrapib decreases pre-β-HDL formation by more than 46%. [1] Anacetrapib potently blocks CE and TG transfer in 95% human serum.[2] |
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In Vivo
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In a dyslipidemic hamster model, 60 mg/kg/day Anacetrapib for 2 weeks results in a 94% reduction in CETP activity and 47% increase in HDL-cholesterol compared with control animals; non-HDL-cholesterol concentrations are not affected. In addition, Anacetrapib promotes reverse cholesterol transport from macrophages, and leads to a 30% increase in fecal cholesterol content. HDL from Anacetrapib-treated hamsters reveals an increase in SR-B1- and ABCG1-mediated efflux compared with controls. [2] After oral administration of [14C]Anacetrapib at 10 mg/kg, ～80 and 90% of the radioactive dose is recovered over 48 hous postdose from rats and monkeys, respectively. The majority of the administered radioactive dose is excreted unchanged in feces in both species. [3] |
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Clinical Trials
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Anacetrapib is in a phase III study among people with established vascular disease. |
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Features
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Protocol
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Kinase Assay
[2]
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| Radioactive assays |
The ability of Anacetrapib to block CETP-mediated CE and TG transfer is measured by radioactive CETP transfer assay with 2% human serum. The procedure is similar to the 95% human serum transfer assay, except that purified human HDL (128 μg/mL) and [3H] cholesteryl oleate or [3H] triolein-labeled LDL are used as acceptor and donor particles, respectively. The [3H] cholesteryl oleate or [3H] triolein from exogenous LDL to HDL is transferred by purified recombinant CETP (30 nM) in standard CETP Buffer (50 mM Tris pH 7.4, 100 nM NaCl, and 1 mM EDTA) with 2% human serum. The transfer reaction is terminated by precipitation of LDL with one volume of ice cold human serum and 2 volumes of 20% W/V PEG 8000. The samples are centrifuged and an aliquot of the HDL-containing supernatant is counted by liquid scintillation. Counts present in the supernatant for controls (without CETP addition) are subtracted from those reactivated with CETP to correct for non-specific transfer. |
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Animal Study
[3]
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| Animal Models |
Adult male Sprague-Dawley rats weighing 280 to 330 g |
| Formulation |
In polyethylene glycol 300-water (7:3, v/v) |
| Doses |
2.5 mL/kg (2.5, 25, 50, 250 mg/mL) |
| Administration |
Oral gavage |
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