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| Targets |
The primary target of JNJ-DGAT2-A is diacylglycerol acyltransferase 2 (DGAT2), an enzyme that catalyzes the final step in triglyceride synthesis. DGAT2 is one of two DGAT isoforms (DGAT1 and DGAT2) that catalyze the acylation of diacylglycerol to form triglycerides. DGAT2 is primarily expressed in the liver and adipose tissue and plays a key role in lipid storage and energy homeostasis. By selectively inhibiting DGAT2, JNJ-DGAT2-A reduces triglyceride synthesis without affecting DGAT1, allowing for targeted investigation of DGAT2-specific pathways.
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| ln Vitro |
Roughly 99% of the activity of the recombinant DGAT2 enzyme is inhibited by JNJ-DGAT2-A (5 μM) [1]. In HepG2 cell lysates, JNJ-DGAT2-A (5 μM) suppresses DGAT activity [1]. TG (52:2), TG (54:3), and TG (50:2) are produced in HepG2 cells using 13C3-D5-glycerol as a substrate. JNJ-DGAT2-A (0.3125, 0.625, 1.25, 2.5, 5, 10, and 20 µM; 60 minutes before isotope labeling and an extra 2 hours after isotope labeling) dose-dependently inhibits this production, with IC50 values of 0.85 μM, 0.99 μM, and 0.66 μM, respectively [1].
In vitro, JNJ-DGAT2-A inhibits the enzymatic activity of recombinant DGAT2 and DGAT2 activity in HepG2 cell lysates with an IC₅₀ of 0.14 μM. It dose-dependently inhibits the generation of the three major triglyceride species in HepG2 cells. This demonstrates potent and selective inhibition of DGAT2 in both cell-free and cellular contexts. The compound's specificity for DGAT2 allows for targeted investigations into pathways influencing energy storage and fat accumulation. |
| ln Vivo |
In vivo, JNJ-DGAT2-A is used to explore therapeutic strategies targeting lipid regulation and energy balance. By inhibiting DGAT2, the compound would be expected to reduce triglyceride synthesis and fat accumulation in vivo, potentially improving metabolic parameters in models of obesity and dyslipidemia. However, specific in vivo efficacy data from animal models is not detailed in the provided sources. The compound advances understanding of DGAT2 biology and metabolic disease mechanisms.
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| Enzyme Assay |
For DGAT2 inhibitors, standard cell-free assays use recombinant DGAT2 enzyme (typically expressed in Sf9 insect cell membranes) and radiolabeled substrates such as [¹⁴C]-diacylglycerol and acyl-CoA. The compound is incubated with the enzyme and substrates, and the incorporation of radiolabel into triglycerides is measured by scintillation counting to determine IC₅₀ values.
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| Cell Assay |
For DGAT2 inhibitors, standard cellular assays use HepG2 cells or other hepatocyte cell lines. Cells are treated with the test compound, and triglyceride synthesis is measured by incorporation of radiolabeled fatty acids (e.g., [¹⁴C]-oleate) into triglycerides, followed by lipid extraction and scintillation counting. Alternatively, cellular triglyceride levels can be quantified by enzymatic assays or mass spectrometry to assess the compound's effects on lipid accumulation.
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| Animal Protocol |
For in vivo evaluation of DGAT2 inhibitors, standard animal models include diet-induced obesity (DIO) models, ob/ob mice, or high-fat diet-fed rodents. The compound is typically administered orally for 2-4 weeks, and endpoints include body weight, adipose tissue mass, hepatic triglyceride content, plasma triglycerides, and glucose tolerance. JNJ-DGAT2-A would be expected to reduce triglyceride synthesis and fat accumulation in these models.
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| ADME/Pharmacokinetics |
JNJ-DGAT2-A has a molecular weight of 523.38 and formula C₂₄H₁₆BrFN₄O₂S. It is soluble in DMSO and other organic solvents. As a small molecule with moderate lipophilicity, it would be expected to have reasonable oral bioavailability and cell permeability. The compound's specificity for DGAT2 allows for targeted investigations into pathways influencing energy storage and fat accumulation. Comprehensive PK studies would be required for therapeutic development.
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| Toxicity/Toxicokinetics |
Detailed toxicology data for JNJ-DGAT2-A is not provided in the available sources. As a research compound targeting lipid metabolism, standard preclinical toxicology would be required for therapeutic development. Inhibition of DGAT2 may have effects on lipid homeostasis in various tissues, and potential effects on intestinal fat absorption, hepatic steatosis, or adipose tissue function would need to be evaluated. The compound is for research use only and not for therapeutic applications.
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| References | |
| Additional Infomation |
JNJ-DGAT2-A is a DGAT2-selective inhibitor with an IC₅₀ of 0.14 μM. It has the molecular formula C₂₄H₁₆BrFN₄O₂S and a molecular weight of 523.38. The chemical name is 3-Bromo-4-[2-fluoro-4-[[4-oxo-2-[[2-(pyridin-2-yl)ethyl]amino]-1,3-thiazol-5-(4H)ylidene]methyl]phenoxy]benzonitrile. It dose-dependently inhibits the generation of the three major TG species in HepG2 cells. No regulatory approval has been identified.
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| Molecular Formula |
C24H16BRFN4O2S
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|---|---|
| Molecular Weight |
523.376846313477
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| Exact Mass |
522.016
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| CAS # |
1962931-71-0
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| PubChem CID |
137025390
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
5.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
816
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N#CC1C=C(Br)C(OC2C(F)=CC(C=C3C(=O)N=C(NCCC4C=CC=CN=4)S3)=CC=2)=CC=1
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| InChi Key |
ZFRHAMOJHTZHLT-XKZIYDEJSA-N
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| InChi Code |
InChI=1S/C24H16BrFN4O2S/c25-18-11-16(14-27)5-6-20(18)32-21-7-4-15(12-19(21)26)13-22-23(31)30-24(33-22)29-10-8-17-3-1-2-9-28-17/h1-7,9,11-13H,8,10H2,(H,29,30,31)/b22-13-
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| Chemical Name |
3-bromo-4-[2-fluoro-4-[(Z)-[4-oxo-2-(2-pyridin-2-ylethylimino)-1,3-thiazolidin-5-ylidene]methyl]phenoxy]benzonitrile
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| Synonyms |
JNJ DGAT2 A JNJDGAT2A JNJ-DGAT2-A
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 : ~3.33 mg/mL (~6.36 mM)
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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 | 1.9107 mL | 9.5533 mL | 19.1066 mL | |
| 5 mM | 0.3821 mL | 1.9107 mL | 3.8213 mL | |
| 10 mM | 0.1911 mL | 0.9553 mL | 1.9107 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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