Anacetrapib is a potent, selective, reversible rhCETP and mutantCETP (C13S) inhibitor with IC50 of 7.9 nM and 11.8 nM, increases HDL-C and decreases LDL-C, does not increase aldosterone or blood pressure.
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.
搜索
