Avasimibe

• Catalog No.: S2187
• CAS Number: 166518-60-1
• M. F.: C29H43NO4S
• M. W.: 501.72102
• Storage: -20°C

SYNONYMS

• IUPAC name: 1-{[2,6-bis(propan-2-yl)phenoxysulfonyl]amino}-2-[2,4,6-tris(propan-2-yl)phenyl]ethan-1-one
• IUPAC Traditional name: 1-[(2,6-diisopropylphenoxysulfonyl)amino]-2-(2,4,6-triisopropylphenyl)ethanone
• Synonyms: CI-1011

DATABASE IDS

• CAS Number: 166518-60-1

PROPERTIES

• Target: ACAT
• Salt Data: Free Base
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Cardiovascular Disease

Biological Activity

• Description: Avasimibe inhibits ACAT and CYP2C9 with IC50 of 3.3 μM and 2.9 μM, respectively.
• Targets:

  ACAT

  ;

  CYP2C9

  ;

  CYP1A2

  ;

  CYP2C19

• IC50:

  3.3 μM ^[1]

  ;

  2.9 μM

  ;

  13.9 μM

  ;

  26.5 μM ^[5]

• In Vitro: Avasimibe at concentration of 1μg/mL causes reduction of Total cholesterol (TC) and Esterified cholesterol (EC) through inhibiting LDL binding and decreasing scavenger receptor numbers during foam cell formation in human monocyte-derived macrophages (HMMs). Avasimibe at concentration of 2μg/mL enhances cholesterol efflux from established HMM foam cells preincubating with 10μg/ml LDL. ^[1] Avasimibe inhibits Lipoprotein(a) accumulation in the culture media of primary monkey hepatocyte in a dose-dependent manner with 11.9% -31.3% inhibition, the change is mainly associated with decreased ApoA. ^[2] Avasimibe incubating at concentration of 10 nM, 1 μM, and 10 μM for 24 hours in HepG2 cells reduce ApoB secretion into media by 25%, 27%, and 43%, respectively. Avasimibe decreases ApoB secretion by enhanced intracellular degradation of ApoB rather than decreased synthesis of ApoB. ^[3] Avasimibe inhibits ACTC with IC50 of 3.3 μM in IC-21 macrophages with consideration of the total inhibitor concentration in the assay sample. ^[4] Avasimibe inhibits human P450 isoenzymes CYP2C9, CYP1A2 and CYP2C19 with IC50 of 2.9 μM, 13.9 μM and 26.5 μM, respectively. ^[5] Avasimibe inhibits ACAT-1 expression and cholesterol ester synthesis in glioma cell lines. Avasimibe inhibits the growth of the glioma cells by inducing cell cycle arrest and apoptosis due to caspase-8 and caspase-3 activation. ^[6]
• In Vivo: Avasimibe significantly reduces Lipoprotein(a) and total cholesterol levels in nine healthy male monkeys with a normal chow diet orally treated with CI-1011 at 30 mg/kg per day for 3 weeks, Lipoprotein(a) and total cholesterol levels reduce to 68 and 73% of control levels, respectively. Avasimibe decreases total cholesterol mainly due to reduction of low density lipoprotein (LDL). ^[2] Avasimibe decreases amyloid plaque load in the cortex and hippocampus and reduces the levels of insoluble Abeta40 and Abeta42 and C-terminal fragments of amyloid precursor protein (APP) in brain extracts in young human APP transgenic mice. Avasimibe reduces diffuse amyloid plaques by suppression of astrogliosis and enhanced microglial activation in aged human APP transgenic mice. ^[7]

Combination Therapy

• Description: Avasimibe at concentration of 0.5 μM enhances atorvastatin caused reduction of esterified cholesterol content at concentration of 5 μM in THP-1 macrophages. ^[8]

Protocol

• Protocol: Kinase Assay ^[1]
• P450 Inhibition Studies: Pooled human liver microsomes (HLM) from at least 15 donors are used for all inhibition assays. For IC50 determinations, the substrate probes are used at their approximate in vitro Km values. All incubations are performed with 100 mM potassium phosphate buffer (pH 7.4) and 1 mM NADPH. For CYP1A2 inhibition study, incubations are performed in a total volume of 0.5 ml, in duplicates with 0.1 mg/ml HLM, 30 μM phenacetin, 1 mM NADPH, and in the presence of avasimibe (0, 0.3, 0.75, 1.5, 3, 7.5, 15, 30, and 40 μM in 50 mM) in a potassium phosphate buffer at pH 7.4. After preincubation at 37 °C for 7 min, NADPH is added to initiate the enzyme reaction. The reaction mixture is quenched with 500 μl of ice-cold 100 ng/ml paracetamol-D₄/CH₃CN after 25 min. The standards (4-acetamidophenol, singlet) and quality controls (triplicates for low, medium, and high) are prepared at room temperature. After mixing, 0.2 ml of the samples is transferred to another plate and submitted for LC/MS/MS analysis after centrifugation at 3000 rpm for 10 min. A Supelco Discovery Amide C16, 100 × 2.1 mm (5-μm particle size) column (Supelco, Bellefonte, PA) is used. The mobile phase is isocratic, 40:60 [acetonitrile/formic acid, 0.1% (v/v)] at 0.2 ml/min.
• Protocol: Animal Study ^[2]
• Animal Models: male cynomolgus monkeys
• Formulation: sterile 0.9% sodium chloride solution
• Doses: 30 mg/kg
• Administration: Orally at a single dose per day for 3 weeks

References

• References: [1] Lee HT, et al. J Med Chem, 1996, 39(26), 5031-5034.
• References: [2] Ramharack R, et al. Atherosclerosis, 1998, 136(1), 79-87.
• References: [3] Wilcox LJ, et al. Arterioscler Thromb Vasc Biol, 1999, 19(4), 939-949.
• References: [4] Rodriguez A, et al. Atherosclerosis, 2002, 161(1), 45-54.
• References: [5] Castillo U, et al. FEMS Microbiol Lett, 2003, 224(2), 183-190.
• References: [6] Bemlih S, et al. Cancer Biol Ther, 2010, 9(12), 1025-1032.
• References: [7] Huttunen HJ, et al. J Neuropathol Exp Neurol, 2010, 69(8), 777-788.
• References: [8] Llaverís G, et al. Eur J Pharmacol, 2002, 451(1), 11-17.

REFERENCES

• Lee HT, et al. J Med Chem, 1996, 39(26), 5031-5034.
• Ramharack R, et al. Atherosclerosis, 1998, 136(1), 79-87.
• Wilcox LJ, et al. Arterioscler Thromb Vasc Biol, 1999, 19(4), 939-949.
• Rodriguez A, et al. Atherosclerosis, 2002, 161(1), 45-54.
• Castillo U, et al. FEMS Microbiol Lett, 2003, 224(2), 183-190.
• Bemlih S, et al. Cancer Biol Ther, 2010, 9(12), 1025-1032.
• Huttunen HJ, et al. J Neuropathol Exp Neurol, 2010, 69(8), 777-788.
• Llaverías G, et al. Eur J Pharmacol, 2002, 451(1), 11-17.