Anacetrapib

SKU: orb1223770

Description

Anacetrapib (MK 0859) is a potent, orally active cholesteryl ester transfer protein (CETP) inhibitor with IC50 of 7.9 nM and 11.8 nM for rhCETP and C13S CETP mutant, respectively; inhibits CETP-mediated cholesterol exchange, resulting in elevated HDL-cholesterol levels and reductions in LDL-cholesterol levels, demonstrates potential to treat elevated cholesterol levels in an effort prevent cardiovascular disease. Atherosclerosis Phase 3 Clinical(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). 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.\n(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. 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. 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 (Cmax) ranges from 5 to 26 μM and the time to reach peak plasma level (Tmax) ranged from 3 to 4.5 h.

Key Properties

• CAS Number: 875446-37-0
• MW: 637.5084
• Purity: >98% (HPLC)
• Formula: C₃₀H₂₅F₁₀NO₃
• SMILES: O=C1O[C@H](C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)[C@H](C)N1CC3=CC(C(F)(F)F)=CC=C3C4=CC(C(C)C)=C(F)C=C4OC
• Target: CETP
• Solubility: 10 mM in DMSO

Bioactivity

• 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. 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. 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 (Cmax) ranges from 5 to 26 μM and the time to reach peak plasma level (Tmax) ranged from 3 to 4.5 h.
• 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). 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.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

MK 0859 | MK-0859 | MK0859

Quick Database Links

Gene Symbol

CETP