Molecule

Description

Hyperlipidaemia, Hypercholesterolaemia , Atherosclerosis

Description

Anacetrapib (MK0859) is a potent and selective rhCETP and mutant CETP(C13S) inhibitor with IC50 of 7.9 nM and 11.8 nM, respectively

Targets

IC₅₀

In Vitro

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]

In Vivo

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]

Clinical Trials

Anacetrapib is in a phase III study among people with established vascular disease.

Features

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.

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