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Avasimibe

ACAT inhibitor,orally bioavailable CAS# 166518-60-1

Avasimibe

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Chemical structure

Avasimibe

3D structure

Chemical Properties of Avasimibe

Cas No. 166518-60-1 SDF Download SDF
PubChem ID 166558 Appearance Powder
Formula C29H43NO4S M.Wt 501.72
Type of Compound N/A Storage Desiccate at -20°C
Synonyms CI-1011; PD-148515
Solubility DMSO : ≥ 28 mg/mL (55.81 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name [2,6-di(propan-2-yl)phenyl] N-[2-[2,4,6-tri(propan-2-yl)phenyl]acetyl]sulfamate
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
Standard InChIKey PTQXTEKSNBVPQJ-UHFFFAOYSA-N
Standard InChI InChI=1S/C29H43NO4S/c1-17(2)22-14-25(20(7)8)27(26(15-22)21(9)10)16-28(31)30-35(32,33)34-29-23(18(3)4)12-11-13-24(29)19(5)6/h11-15,17-21H,16H2,1-10H3,(H,30,31)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Avasimibe

DescriptionAvasimibe is an orally bioavailable inhibitor of ACAT with IC50 value of 3.3 μM.
TargetsACAT    
IC503.3 μM     

Avasimibe Dilution Calculator

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Avasimibe Molarity Calculator

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Preparing Stock Solutions of Avasimibe

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9931 mL 9.9657 mL 19.9314 mL 39.8629 mL 49.8286 mL
5 mM 0.3986 mL 1.9931 mL 3.9863 mL 7.9726 mL 9.9657 mL
10 mM 0.1993 mL 0.9966 mL 1.9931 mL 3.9863 mL 4.9829 mL
50 mM 0.0399 mL 0.1993 mL 0.3986 mL 0.7973 mL 0.9966 mL
100 mM 0.0199 mL 0.0997 mL 0.1993 mL 0.3986 mL 0.4983 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Avasimibe

Avasimibe is an orally bioavailable inhibitor of the acyl coenzyme A: cholesterol acyltransferase (ACAT) with IC50 value of 60nM [1].

Avasimibe is developed from a strategy to design ACAT inhibitors with improved bioavailability. It also has solution stability at acidic pH. In the in vitro assay, the IC50 value is dependent on the concentration of microsomes, the amount of membrane available for adsorption as well as the presence of BSA. The treatment of avasimibe during the process of lipid loading causes a concentration-dependent reduction in cellular cholesteryl ester content. This reduction is not accompanied by the accumulation of intracellular free cholesterol, indicating a better safety profile for avasimibe than other ACAT inhibitors. Avasimibe can also reduce the synthesis and secretion of Apo B 100 (a component of VLDL) in HepG2 cells. In addition, avasimibe can increase the total bile acid synthesis in rat hepatocytes at the concentration of 3μM [1].

Apart from the antiatherosclerotic efficacy, avasimibe is also found to take participate in the modulation of APP trafficking. It can delay and reduce the maturation of APP, limiting the availability of APP holoprotein for Aβ-generatiion [2].

References:
[1] Llaverías G, Laguna JC, Alegret M. Pharmacology of the ACAT inhibitor avasimibe (CI-1011). 2003 Spring;21(1):33-50.
[2] Huttunen HJ, Peach C, Bhattacharyya R, Barren C, Pettingell W, Hutter-Paier B, Windisch M, Berezovska O, Kovacs DM. Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J. 2009 Nov;23(11):3819-28.

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References on Avasimibe

Avasimibe encapsulated in human serum albumin blocks cholesterol esterification for selective cancer treatment.[Pubmed:25662106]

ACS Nano. 2015 Mar 24;9(3):2420-32.

Undesirable side effects remain a significant challenge in cancer chemotherapy. Here we report a strategy for cancer-selective chemotherapy by blocking acyl-CoA cholesterol acyltransferase-1 (ACAT-1)-mediated cholesterol esterification. To efficiently block cholesterol esterification in cancer in vivo, we developed a systemically injectable nanoformulation of Avasimibe (a potent ACAT-1 inhibitor), called avasimin. In cell lines of human prostate, pancreatic, lung, and colon cancer, avasimin significantly reduced cholesteryl ester storage in lipid droplets and elevated intracellular free cholesterol levels, which led to apoptosis and suppression of proliferation. In xenograft models of prostate cancer and colon cancer, intravenous administration of avasimin caused the concentration of Avasimibe in tumors to be 4-fold higher than the IC50 value. Systemic treatment of avasimin notably suppressed tumor growth in mice and extended the length of survival time. No adverse effects of avasimin to normal cells and organs were observed. Together, this study provides an effective approach for selective cancer chemotherapy by targeting altered cholesterol metabolism of cancer cells.

Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions.[Pubmed:15533865]

Circulation. 2004 Nov 23;110(21):3372-7.

BACKGROUND: Inhibition of the acyl coenzyme A:cholesterol acyltransferase (ACAT) enzyme may prevent excess accumulation of cholesteryl esters in macrophages. The ACAT inhibitor Avasimibe was shown to reduce experimental atherosclerosis. This study was designed to investigate the effects of Avasimibe on human coronary atherosclerosis. METHODS AND RESULTS: This randomized, double-blind, placebo-controlled trial assessed the effects of Avasimibe at dosages of 50, 250, and 750 mg QD on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). All patients received background lipid-lowering therapy if necessary to reach a target baseline LDL level <125 mg/dL (3.2 mmol/L). IVUS and coronary angiography were performed at baseline and repeated after up to 24 months of treatment. Approximately equal percentages of patients across groups received concurrent statin therapy (87% to 89%). The mean total plaque volume at baseline was approximately 200 mm3, and the least squares mean change at end of treatment was 0.7 mm3 for placebo and 7.7, 4.1, and 4.8 mm3 for the Avasimibe 50, 250, and 750 mg groups, respectively (adjusted P=0.17 [unadjusted P=0.057], 0.37, and 0.37, respectively). Percent atheroma volume increased by 0.4% with placebo and by 0.7%, 0.8%, and 1.0% in the respective Avasimibe groups (P=NS). LDL cholesterol increased during the study by 1.7% with placebo but by 7.8%, 9.1%, and 10.9% in the respective Avasimibe groups (P<0.05 in all groups). CONCLUSIONS: Avasimibe did not favorably alter coronary atherosclerosis as assessed by IVUS. This ACAT inhibitor also caused a mild increase in LDL cholesterol.

Acyl-coenzyme A: cholesterol acyltransferase inhibitor Avasimibe affect survival and proliferation of glioma tumor cell lines.[Pubmed:20404512]

Cancer Biol Ther. 2010 Jun 15;9(12):1025-32. Epub 2010 Jun 24.

Glioblastoma is the most common primary brain tumor in adults and one of its hallmarks is resistance to apoptosis. Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular membrane-bound enzyme that uses cholesterol and long chain fatty acyl-CoA as substrates to produce cholesteryl esters. The presence of cholesteryl esters in glioblastoma may be related to vascular and/or cell neoplastic proliferation in the tumor mass, two prerequisites for tumor cell growth. ACAT activity has been detected in glioblastoma cell homogenates. The present study is the first report on the effect of Avasimibe, a specific inhibitor of ACAT, on glioma cell lines (U87, A172 and GL261). Our results showed that Avasimibe inhibited ACAT-1 expression and cholesterol ester synthesis in glioma cell lines. Moreover, Avasimibe inhibited the growth of the cells by inducing cell cycle arrest and induced apoptosis as a result of caspase-8 and caspase-3 activation. Also, Our findings provide proof of principle that targeting ACAT-1 with the inhibitor Avasimibe could be an efficient therapy in the treatment of glioblastoma.

The ACAT inhibitor avasimibe increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs.[Pubmed:16427354]

Biochim Biophys Acta. 2005 Dec 30;1738(1-3):10-8.

Previously, we have shown, in vivo, that the acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitor Avasimibe decreases hepatic apolipoprotein (apo) B secretion into plasma. To test the hypothesis that Avasimibe modulates postprandial triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg) containing retinol was given to 9 control miniature pigs and to 9 animals after 28 days treatment with Avasimibe (10 mg/kg/day, n=5; 25 mg/kg/day, n=4). The kinetic parameters for plasma retinyl palmitate (RP) metabolism were determined by multi-compartmental modeling using SAAM II. Avasimibe decreased the 2-h TRL (d<1.006 g/mL; S(f)>20) triglyceride concentrations by 34%. The TRL triglyceride 0-12 h area under the curve (AUC) was decreased by 21%. In contrast, Avasimibe had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma, however, the TRL RP 0-12 h AUC was decreased by 17%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate (FCR) was increased 1.4-fold with Avasimibe. The TRL RP FCR was negatively correlated with very low density lipoprotein (VLDL) apoB production rate measured in the fasting state (r=-0.504). No significant changes in total intestinal lipid concentrations were observed. Thus, although Avasimibe had no effect on intestinal TRL secretion, plasma TRL clearance was significantly increased; an effect that may relate to a decreased competition with hepatic VLDL for removal processes.

Description

Avasimibe is an oral inhibitor of acyl-Coenzyme A:cholesterol acyltransferase (ACAT) with IC50s of 24 and 9.2 µM for ACAT1 and ACAT2, respectively.

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