Home Metabolism P450 (e.g. CYP17) inhibitor - Acyltransferase inhibitor Avasimibe For research use only.

Avasimibe

Synonyms: CI-1011, PD-148515

Avasimibe inhibits ACAT with IC50 of 3.3 μM, also inhibits human P450 isoenzymes CYP2C9, CYP1A2 and CYP2C19 with IC50 of 2.9 μM, 13.9 μM and 26.5 μM, respectively.

Avasimibe Chemical Structure

Avasimibe Chemical Structure

CAS: 166518-60-1

Selleck's Avasimibe has been cited by 19 Publications

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Purity & Quality Control

Batch: Purity: 99.95%
99.95

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Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
THP1 cells Function assay Inhibition of ACAT-mediated esterified cholesterol accumulation in human THP1 cells exposed to acetyl-LDL during differentiation assessed as effect on foam cell formation, IC50=1.5 μM 18620381
HepG2 cells Function assay Inhibition of ACAT in human HepG2 cells, IC50=0.479 μM 19167888
rat macrophages Function assay 24 h Inhibition of ACAT in rat macrophages assessed as incorporation of extracellular [3H]-oleic acid-BSA complex into the intracellular cholesteryl ester after 24 hrs, IC50=0.479 μM 19464189
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells 29435139
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells 29435139
NB-EBc1 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells 29435139
Saos-2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
IC21 Function assay Inhibition of ACAT1 in mouse IC21 cells in absence of BSA, IC50=0.06μM 29945757
J774 Function assay 18 hrs Inhibition of ACAT1 in mouse J774 cells assessed as reduction in esterified cholesterol accumulation after 18 hrs in presence of 25-hydroxycholesterol, IC50=0.59μM 29945757
IC21 Function assay Inhibition of ACAT1 in mouse IC21 cells in presence of BSA, IC50=0.76μM 29945757
Caco-2 Function assay 48 hrs Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells after 48 hours by high content imaging, IC50=3.93μM ChEMBL
Caco-2 Toxicity assay 48 hrs Toxicity against Caco-2 cells determined at 48 hours by intracellular ATP concentration using the CellTiter-Glo Luminescent Cell Viability Assay, CC50=13.71μM ChEMBL
Click to View More Cell Line Experimental Data

Biological Activity

Description Avasimibe inhibits ACAT with IC50 of 3.3 μM, also inhibits human P450 isoenzymes CYP2C9, CYP1A2 and CYP2C19 with IC50 of 2.9 μM, 13.9 μM and 26.5 μM, respectively.
Targets
CYP2C9 [5]
(Human Hepatic Microsomes)		 ACAT [1]
(IC-21 macrophages)		 CYP1A2 [5]
(Human Hepatic Microsomes)		 CYP2C19 [5]
(Human Hepatic Microsomes)
2.9 μM 3.3 μM 13.9 μM 26.5 μM
In vitro
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]
Kinase Assay 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.
Cell Research Cell lines primary human monocyte-derived macrophages
Concentrations 1 μg/mL or 2 μg/mL
Incubation Time 48 hours
Method

For foam cell formation, the growth medium (RPMI medium containing 10% human serum) is aspirated and the BMMs are rinsed four times with RPMI medium, and then HMMs are exposed to RPMI medium containing bovine serum albumin (BSA, 0.2%) and dimethylsulfoxide (DMSO, 0.2%, vehicle for CI-1011) (control medium) with and without agacLDL (100 μg protein/ml) and CI-1011 (1 μg/ml) for 48 hours. For cholesterol efflux experiments, HMMs are preincubated with ag-acLDL (100 μg protein/ml) for 24h, and then exposed to control RPMI medium with and without HDL (100 μg protein/ml), CI-1011 (2 μg/ml) or HDL plus CI-1011 (2 μg/ml) for 24–48 hours. Additionally, the appearance of [14C]FC in the medium is monitored by first preincubating HMMs with RPMI medium containing ag-acLDL (100 μg protein/ml) radiolabeled with [4-14C]FC (0.5 μCi/ml) in an ethanolic spritz (final concentration, 0.1%) for 24 h. The medium is removed, cells rinsed three times with RPMI medium, and then cells are exposed to control RPMI medium with and without CI-1011 (1–10 μg/ml) for 4–48 h. At each time point, the medium is aspirated and centrifuged to pellet nonadherent cells. The appearance of [14C]FC in the medium is measured by liquid scintillation spectroscopy. Cellular lipids are extracted using hexane:isopropanol (3:2, v/v) for 1 h. The distribution of cellular radiolabeled cholesterol is measured by subjecting an aliquot of the cell extract and FC and EC standards to thin layer chromatography using petroleum ether:hexane:glacial acetic acid solvent system (85:15:2, v/v). The percent FC efflux is calculated as: medium [14C]FC dpm/ cell [14C] dpm×100. FC and TC mass are quantified by gas liquid chromatography using stigmasterol (1 mg/ml) as an internal standard. EC mass is calculated as the difference between TC and FC, and all values are normalized to cell protein. The MBC is defined as the lowest concentration that exhibited 99.9% or more reduction of the numbers of colonies compared with the cfu in the initial inoculum.
Experimental Result Images Methods Biomarkers Images PMID
Western blot p-AKT / AKT Active β-catenin 29489864
Immunofluorescence β-catenin 29545473
In Vivo
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]
Animal Research Animal Models male cynomolgus monkeys
Dosages 30 mg/kg
Administration Orally at a single dose per day for 3 weeks

Chemical lnformation & Solubility

Molecular Weight 501.72 Formula

C29H43NO4S
CAS No. 166518-60-1 SDF Download Avasimibe SDF
Smiles CC(C)C1=C(C(=CC=C1)C(C)C)OS(=O)(=O)NC(=O)CC2=C(C=C(C=C2C(C)C)C(C)C)C(C)C
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 100 mg/mL ( (199.31 mM)； Warmed with 50°C water bath; Ultrasonicated; Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 16 mg/mL

Water : Insoluble


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In vivo
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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

Question 1:
I'd like to have more information about the in vivo administration of avasimibe in monkeys?

Answer:
S2187 can be dissolved in 2% DMSO+corn oil at 5mg/ml clearly, and in 0.5% CMC Na+1% Tween 80 at 10mg/ml as a suspension.

Question 2:
We want to use it for mice study by IP injection. I was wondering if you have any suggestions how to make a soluble solution for IP injection?

Answer:
S2187 Avasimibe can be dissolved in 5% DMSO+30% PEG 300+5% Tween 80+ddH2O at 1 mg/ml as a clear solution. When preparing the solution, please dissolve the compound in DMSO clearly first, then add PEG and Tween. After they mixed well, then dilute with water. And we found after stayed for about 20min, the precipitation will go out. So please prepare the solution just before use.

P450 (e.g. CYP17) Signaling Pathway Map

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