Anacetrapib

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. IC50 & Target: IC50: 7.9±2.5 nM (rhCETP), 11.8±1.9 nM (CETP^C13S)^[1] In Vitro: Anacetrapib dose-dependently and significantly decreases the transfer of CE from HDL3 to HDL2 (P<0.001 for concentrations equal to and higher than 0.1 μM). Excess Anacetrapib (25 μM) decreases the amount of [¹⁴C]Torcetrapib (0.25 μM) binds to immobilized rhCETP by 82% and 60%, respectively. Anacetrapib decreases pre-β-HDL formation by more than 46% (P<0.001) at all concentrations tested (0.1, 1, 3, and 10 μM)^[1]. A significant reduction of PCSK9 promoter activity by Anacetrapib (ANA) is detected at 3 μM concentration (?22%, p<0.01) and further lowered to 68% of control at 10 μM. Likewise, luciferase activity of B11 cells are decreased by Anacetrapib at 3 μM concentration and reached to a maximal reduction of 38% of control at 10 μM. At 10 μM concentration, Anacetrapib loweres PCSK9 mRNA level to 60% of control and LDLR mRNA level to 67% of control^[2]. In Vivo: Hamsters are given Anacetrapib for 7 days before injection of [³H]cholesterol-labeled macrophages (day 0). Treatment with Anacetrapib leads to significant increases in HDL-C levels at day 0. At day 3, [³H]cholesterol radioactivity in the HDL fraction is significantly increased from control values for Anacetrapib^[1]. Anacetrapib (ANA) treatment modestly elevates serum total serum cholesterol levels ~10% (p<0.05) and increases serum LDL-C by 26% (p<0.05) as compared to vehicle control^[2]. After an intravenous dose of 0.5 mg/kg, the mean values for systemic plasma clearance, steady-state volume of distribution, and terminal half-life are 2.3 mL/min/kg, 1.1 L/kg, and 12 h, respectively. After oral dosing at 5 mg/kg, the bioavailability of Anacetrapib is 38%. Exposures (AUC) increases in a less than dose-proportional manner from 23 μM?h at 5 mg/kg to 362 μM?h at 500 mg/kg. In this dose range, the peak plasma level (C_max) ranges from 5 to 26 μM and the time to reach peak plasma level (T_max) ranged from 3 to 4.5 h^[3].