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Purity: ≥98%
SB 204990, the prodrug of the ATP citrate-lyase inhibitor SB-201076, is a potent, orally available and specific inhibitor of ATP citrate lyase (ACLY) enzyme. SB-204990 (25 mg/kg per day) also decreased plasma cholesterol levels (by up to 23%) and triglyceride levels (by up to 38%) in the dog, preferentially decreasing low-density lipoprotein compared with high-density lipoprotein cholesterol levels. SB-204990 is an important enzyme in controlling substrate supply for lipid synthesis de novo and a potential enzyme target for hypolipidaemic intervention.
| Targets |
SB-204990 is a specific inhibitor of ATP citrate lyase (ACLY) [1]
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| ln Vitro |
The ACLY enzyme is specifically inhibited by SB204990 (SB). Acetylation and active β-catenin levels are predicted to decrease as a result of SB204990 therapy, which lowers cytosolic Ac-CoA levels [1].
In C3H10T1/2 cells, treatment with 100 µM SB-204990 for 48 hours reversed the galactose-induced activation of β-catenin reporter activity and the expression of β-catenin target genes Axin2 and Dkk1. [1] Treatment with 100 µM SB-204990 for 48 hours also reversed the increase in acetylated β-catenin levels induced by galactose treatment in C3H10T1/2 cells, as detected by immunoprecipitation. [1] In MC3T3-E1 osteogenic cells, the galactose-induced increases in mineralization (alizarin red staining) and β-catenin activity (TopFlash reporter) were reversed by inhibition of ACLY with SB-204990. [1] |
| ln Vivo |
Oral administration of SB 204990 to rats results in its absorption into the systemic circulation. Rats given SB 204990 in the diet (0.05-0.25%, w/w) for one week experienced dose-related decreases in plasma cholesterol (up to 46%) and triglyceride levels (up to 80%). By preferentially lowering LDL cholesterol levels over HDL cholesterol levels, SB 204990 (25 mg/kg daily) also lowers triglyceride levels (up to 38%) and plasma cholesterol levels (up to 23%) in dogs [2].
In male Sprague-Dawley rats, intravenous administration of SB-204990 (two doses of 150 µmol/kg each, 245 and 65 minutes before measurement) inhibited hepatic cholesterol synthesis by 76% and fatty acid synthesis by 39% compared to vehicle control. [2] Oral administration of SB-204990 mixed into the diet (0.05%, 0.125%, and 0.25% w/w) for 1 week caused dose-related decreases in plasma cholesterol (up to 46%) and triglycerides (up to 80%) in rats. Concurrently, the rate of hepatic very-low-density lipoprotein (VLDL) synthesis, measured by the Triton WR-1339 method, was decreased by up to 48%. [2] In male beagle dogs, oral administration of SB-204990 (10 mg/kg/day for 7 days, then 25 mg/kg/day for 15 days) in gelatin capsules caused significant and sustained decreases in fasting plasma cholesterol (up to 23%) and triglycerides (up to 38%). The effect was greater on low-density lipoprotein (LDL) cholesterol (40% decrease) than on high-density lipoprotein (HDL) cholesterol (22% decrease). Plasma lipid levels returned to pretreatment levels after cessation of treatment. [2] |
| Enzyme Assay |
ATP citrate-lyase (ACLY) activity was determined by a coupled enzymatic assay. The reaction, catalyzed by ACLY, cleaves citrate into acetyl-CoA and oxaloacetate. The oxaloacetate produced is then reduced by malate dehydrogenase, consuming NADH. The decrease in absorbance at 340 nm, corresponding to NADH consumption, is monitored over 20 minutes to measure enzyme activity. Assays were conducted at the Km for citrate (100 µM) and with saturating concentrations of ATP (250 µM) and CoA (200 µM). Inhibition studies were performed using purified rat liver ACLY or recombinant human ACLY. [2]
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| Cell Assay |
C3H10T1/2 and MC3T3-E1 cells were cultured in low-glucose DMEM. To inhibit ACLY and thus β-catenin acetylation, cells were treated with SB-204990 at a concentration of 100 µM. Cells were incubated in glucose or galactose medium for 48 hours before collection. Galactose was used to force cells to rely on mitochondrial oxidative phosphorylation. [1]
For β-catenin acetylation analysis, cell lysates were immunoprecipitated with an anti-β-catenin antibody, and the immunoprecipitates were probed with an anti-acetylated lysine antibody. [1] For β-catenin activity measurement, cells were transfected with the TopFlash (β-catenin) luciferase reporter and a Renilla luciferase control vector. After 48 hours of treatment, cells were lysed, and firefly luciferase activity was measured and normalized to Renilla luciferase activity. [1] |
| Animal Protocol |
Rat - Lipid Synthesis Inhibition: Male Sprague-Dawley rats were used. SB-204990 or vehicle (rat serum) was administered via intravenous injection at doses of 2 × 150 µmol/kg, given 245 and 65 minutes before the intraperitoneal injection of ³H₂O. Hepatic cholesterol and fatty acid synthesis rates were measured over the subsequent 65 minutes before tissue collection. [2]
Rat - Hypolipidemic Study: Rats were fed a standard powdered diet mixed with SB-204990 at concentrations of 0.05%, 0.125%, or 0.25% (w/w) for 1 week. Food intake and body weight were recorded daily. Plasma lipids were measured from tail vein blood. VLDL synthesis rate was determined by injecting Triton WR-1339 intravenously and measuring the increase in plasma triglyceride 90 minutes later. [2] Rat - Bioavailability Study: A single oral dose of [³H]SB-204990 (150 µmol/kg) was administered by gavage. Animals were sacrificed at 2, 4, and 6 hours post-dose. Plasma, liver, and kidney were collected. Tissue homogenates and plasma were extracted with acetonitrile, and the levels of SB-204990 and its active form SB-201076 were quantified by HPLC with radiometric detection. [2] Dog - Hypolipidemic Study: Male beagle dogs received SB-204990 orally once daily in gelatin capsules. The dosing regimen was 10 mg/kg/day for 7 days, followed by 25 mg/kg/day for 15 days. Blood samples were collected from the cephalic vein before the morning meal. Plasma was analyzed for total cholesterol, triglycerides, and lipoprotein fractions (VLDL, LDL, HDL) isolated by sequential ultracentrifugation. [2] |
| ADME/Pharmacokinetics |
In rats, following a single oral administration of [³H]SB-204990 (150 µmol/kg), the prodrug SB-204990 and its active metabolite SB-201076 were detected in plasma, liver, and kidney. The plasma concentration of SB-201076 peaked at 4 hours (41 nmol/mL). Higher liver concentrations were observed, with peak concentrations of 173 nmol/g for SB-204990 and 87 nmol/g for SB-201076 at 4 hours. These liver concentrations of SB-201076 were significantly higher than its Ki value for ACLY (1 µM). Four hours after administration, 21% of the radiolabeled material was recovered in the liver, 3.5% in plasma, and 1% in the kidney. [2]
In a study on lipid-lowering in rats, after one week of dietary administration, the concentration of SB-204990 in the liver was dose-dependent, ranging from 60 to 103 nmol/g. [2] |
| References |
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| Additional Infomation |
This study used SB-204990 as a pharmacological tool to inhibit ACLY. ACLY reduces cytoplasmic citrate exported from active mitochondria to acetyl-CoA. This ACLY-derived cytoplasmic acetyl-CoA is acetylated by acetyltransferases (e.g., p300, CBP, PCAF) and activates β-catenin. Inhibition of ACLY with SB-204990 disrupts the link between mitochondrial oxidative phosphorylation and β-catenin acetylation, thereby reducing osteogenic differentiation. [1]
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| Molecular Formula |
C18H22CL2O5
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|---|---|
| Molecular Weight |
389.2703
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| Exact Mass |
388.084
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| CAS # |
154566-12-8
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| PubChem CID |
10340264
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| Appearance |
White to off-white solid powder
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| LogP |
4.007
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
25
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| Complexity |
472
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C1[C@H](OC(=O)[C@]1(CC(=O)O)O)CCCCCCC2=C(C=C(C=C2)Cl)Cl
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| InChi Key |
YTRNLFYTHYWDAU-RDTXWAMCSA-N
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| InChi Code |
InChI=1S/C18H22Cl2O5/c19-13-8-7-12(15(20)9-13)5-3-1-2-4-6-14-10-18(24,11-16(21)22)17(23)25-14/h7-9,14,24H,1-6,10-11H2,(H,21,22)/t14-,18-/m1/s1
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| Chemical Name |
trans-5-[6-(2,4-Dichlorophenyl)hexyl]tetrahydro-3-hydroxy-2-oxo-3-furanacetic acid
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| Synonyms |
SB-204990; SB 204990; SB204990
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (~256.89 mM)
H2O : ~25 mg/mL (~64.22 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2.56 mg/mL (6.58 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5689 mL | 12.8446 mL | 25.6891 mL | |
| 5 mM | 0.5138 mL | 2.5689 mL | 5.1378 mL | |
| 10 mM | 0.2569 mL | 1.2845 mL | 2.5689 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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