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NB-598 hydrochloride is a novel, highly potent and competitive inhibitor of squalene epoxidase (SE), suppressing triglyceride biosynthesis through the farnesol pathway. NB-598 significantly inhibited both basal and glucose-stimulated insulin secretion from mouse pancreatic islets. CaV channels were markedly inhibited by NB-598.
| Targets |
SE/squalene epoxidase
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|---|---|
| ln Vitro |
In MIN6 cells, NB598 (10 μM) decreased total cholesterol levels by 36±7%. In PM, ER, and SG, NB598 significantly decreased cholesterol by 49±2%, 46±7%, and 48±2%, respectively. Under both basal (1 mM glucose) and glucose-stimulated (16.7 mM glucose) conditions, NB598 dose-dependently inhibits insulin secretion. At concentrations up to 10 μM, NB598 increases current deactivation but has no effect on peak outward KV current or the voltage dependence of activation [1]. The synthesis of sterols and sterol esters from [14C]acetate is inhibited by NB-598 (10 μM), while other lipids like phospholipids (PL), free fatty acids (FFA), and triacylglycerols (TG) are not affected. NB-598 decreased ACAT activity by 31% when exogenous liposomal cholesterol was not present. Even at 600 PM liposomal cholesterol concentration, NB-598 caused a 22% reduction in ACAT activity[2]. HepG2 cells' secretion of triacylglycerol and cholesterol into the culture medium is inhibited by NB-598 [3].
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| ln Vivo |
NB-598, (E)N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bith iophen-5-yl)methoxy]benzene-methanamine, was found to inhibit human microsomal squalene epoxidase (from Hep G2 cells) in a competitive manner. NB-598 inhibited cholesterol synthesis from [14C]acetate dose dependently in Hep G2 cells and increased the intracellular radioactivity of squalene. A single oral administration of NB-598 inhibited cholesterol synthesis from [14C]acetate in rats. Moreover, multiple oral administration of NB-598 to dogs decreased serum total and low density lipoprotein cholesterol levels and increased serum squalene levels. After termination of treatment, the reduced serum cholesterol and increased squalene levels returned to their control values[4].
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| Enzyme Assay |
NB-598, a specific inhibitor of squalene epoxidase, suppressed the secretion of cholesterol and triacylglycerol from HepG2 cells into the medium. L-654,969, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, inhibited the secretion of cholesterol as potently as NB-598, but did not suppress the secretion of triacylglycerol. Both compounds decreased the intracellular cholesterol content almost equally, and neither of the compounds reduced the intracellular triacylglycerol content. The suppression of lipid secretion by NB-598 was associated with a significant reduction in apolipoprotein (apo) B secretion into the medium. Therefore, the suppression of lipid secretion by NB-598 may be caused by a reduction in the number of triacylglycerol-rich lipoprotein particles. In contrast, the suppression of cholesterol secretion by L-654,969 may be due to a modulation of lipoprotein lipid composition, since this agent did not reduce the secretion of apo B or triacylglycerol. The secretion of apo A-I was unaffected by either NB-598 or L-654,969. Pulse chase studies using [35S]methionine showed that the suppression of apo B secretion by NB-598 depended on an enhancement of intracellular degradation of apo B. These results indicate that the secretion of apo B from HepG2 cells is not regulated by the lipid synthesis alone, and suggest that the mechanism of the hypolipidemic effect of NB-598 involves the suppression of triacylglycerol-rich lipoprotein secretion from the liver as well as an inhibition of cholesterol synthesis in the liver[3].
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| Cell Assay |
Subcellular fractionation of plasma membranes, endoplasmic reticulum, and insulin secretory granules[1]
MIN6 cells (4 × 108) were cultured for 48 h at 37 C in the culture medium supplemented with 10% delipidated FBS, in the absence or presence of 10 μM NB598. The cells were harvested and homogenized in fractionation buffers: 50 mM 2-(N-morpholino) ethane sulfonic acid (MES), 250 mM sucrose (pH 7.2) for plasma membrane (PM) and endoplasmic reticulum (ER); 10 mM 3[N-morholino]propanesulfonic acid-Tris, 270 mM sucrose (pH 6.8) for insulin secretory granules (SG). Fractionations for PM and ER were performed by sucrose density gradient ultracentrifugation established by Ramanadham et al. Insulin secretory granules were fractionated with Histodenz gradient ultracentrifugation followed by Percoll purification, as established by Brunner et al. The isolated subcellular fractions were stored at −20 C for protein concentration determination and cholesterol extraction.
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| References |
[1]. Xia F, et al. Inhibition of cholesterol biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic beta-cells. Endocrinology. 2008 Oct;149(10):5136-45.
[2]. Horie M, et al. Effects of NB-598, a potent squalene epoxidase inhibitor, on the apical membrane uptake of cholesterol and basolateral membrane secretion of lipids in Caco-2 cells. Biochem Pharmacol. 1993 Jul 20;46(2):297-305. [3]. Horie M, et al. An inhibitor of squalene epoxidase, NB-598, suppresses the secretion of cholesterol and triacylglycerol and simultaneously reduces apolipoprotein B in HepG2 cells. Biochim Biophys Acta. 1993 May 20;1168(1):45-51. [4]. NB-598: a potent competitive inhibitor of squalene epoxidase. J Biol Chem . 1990 Oct 25;265(30):18075-8. |
| Molecular Formula |
C6H13N
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|---|---|
| Molecular Weight |
99.1741216182709
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| Exact Mass |
485.161
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| Elemental Analysis |
C, 66.71; H, 6.64; Cl, 7.29; N, 2.88; O, 3.29; S, 13.19
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| CAS # |
136719-25-0
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| Related CAS # |
NB-598;131060-14-5;NB-598 Maleate;155294-62-5
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| PubChem CID |
19744556
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
8.285
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
32
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| Complexity |
628
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCN(C/C=C/C#CC(C)(C)C)CC1=CC=CC(OCC2=CC(C3=CSC=C3)=CS2)=C1.[H]Cl
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| InChi Key |
WDXQLZXORYGXJN-WVLIHFOGSA-N
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| InChi Code |
InChI=1S/C27H31NOS2.ClH/c1-5-28(14-8-6-7-13-27(2,3)4)18-22-10-9-11-25(16-22)29-19-26-17-24(21-31-26)23-12-15-30-20-23;/h6,8-12,15-17,20-21H,5,14,18-19H2,1-4H3;1H/b8-6+;
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| Chemical Name |
(E)-N-ethyl-6,6-dimethyl-N-[[3-[(4-thiophen-3-ylthiophen-2-yl)methoxy]phenyl]methyl]hept-2-en-4-yn-1-amine;hydrochloride
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| Synonyms |
NB-598 (hydrochloride); 136719-25-0; NB-598 hydrochloride; (E)-N-ethyl-6,6-dimethyl-N-[[3-[(4-thiophen-3-ylthiophen-2-yl)methoxy]phenyl]methyl]hept-2-en-4-yn-1-amine;hydrochloride; NB-598hydrochloride; SCHEMBL408927; SCHEMBL408929; DTXSID30599492;
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 10.0837 mL | 50.4185 mL | 100.8369 mL | |
| 5 mM | 2.0167 mL | 10.0837 mL | 20.1674 mL | |
| 10 mM | 1.0084 mL | 5.0418 mL | 10.0837 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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