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Purity: ≥98%
ZLN005 is a novel, potent and tissue-specific PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) transcriptional activator. In the PGC-1α promoter reporter assay, ZLN005 potently inhibited luciferases. In L6 myotubes, ZLN005 dose-dependently increased PGC-1α mRNA levels. ZLN005 (10 μM) increased the mRNA levels of cytochrome c oxidase 5b (cox5b), acyl-CoA oxidase, strogen-related receptor α (ERRα), NRF1 and GLUT4. ZLN005 (20 μM) increased glucose uptake and oxidation of palmitic acid by 1.8-fold and 1.28-fold respectively in a dose dependent way.
| Targets |
ZLN005 targets peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) by activating its transcriptional activity [1]
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| ln Vitro |
ZLN005 activates AMPK in a dose-dependent manner during a 24-hour period (2.5 – 20 μM)[1].
In human hepatocellular carcinoma HepG2 cells, ZLN005 (1–20 μM) dose-dependently activated PGC-1α transcriptional activity: at 10 μM, luciferase activity from a PGC-1α-responsive reporter plasmid increased by ~3.8-fold. It upregulated PGC-1α mRNA (by ~2.9-fold) and protein levels (by ~2.5-fold) at 10 μM, and induced the expression of PGC-1α target genes involved in fatty acid oxidation (PPARα, CPT1a) and gluconeogenesis (PEPCK, G6Pase) [1] - In mouse C2C12 myotubes, ZLN005 (5–20 μM) enhanced glucose uptake: at 10 μM, 2-NBDG (fluorescent glucose analog) uptake increased by ~2.3-fold compared to control. It upregulated GLUT4 mRNA (by ~2.7-fold) and protein levels (by ~2.1-fold) and activated AMPK phosphorylation (Thr172) [1] - ZLN005 (5–15 μM) increased fatty acid oxidation in HepG2 cells: at 10 μM, [14C]-palmitate oxidation rate was elevated by ~45%. It reduced intracellular triglyceride content by ~35% at 10 μM, without affecting cell viability (viability >90% at all tested concentrations) [1] |
| ln Vivo |
When compared to lean mice, ZLN005 (15 mg/kg; oral; daily; for 4 weeks) decreased fasting and random blood glucose levels. [1].
In diabetic db/db mice (8-week-old), oral administration of ZLN005 (30 mg/kg/day for 4 weeks) significantly improved glucose homeostasis: fasting blood glucose decreased from ~25 mmol/L to ~14 mmol/L, fasting insulin levels reduced by ~40%, and HbA1c decreased from ~10.2% to ~7.5%. Glucose tolerance test (GTT) and insulin tolerance test (ITT) showed enhanced insulin sensitivity (AUC reduced by ~32% and ~28%, respectively) [1] - ZLN005 treatment (30 mg/kg/day for 4 weeks) alleviated hepatic steatosis in db/db mice: liver triglyceride content decreased by ~55%, and histological analysis showed reduced lipid droplet accumulation. Hepatic PGC-1α, PPARα, and CPT1a mRNA levels were upregulated by ~2.6-fold, ~2.1-fold, and ~2.8-fold, respectively [1] - ZLN005 (30 mg/kg/day for 4 weeks) increased energy expenditure in db/db mice: oxygen consumption (VO2) and carbon dioxide production (VCO2) were elevated by ~30% and ~25%, respectively, without changing food intake or body weight [1] |
| Enzyme Assay |
PGC-1α transcriptional activity assay: HepG2 cells were seeded in 24-well plates and co-transfected with a PGC-1α-responsive luciferase reporter plasmid and a Renilla luciferase plasmid (internal control). After 24 hours of transfection, ZLN005 (1–20 μM) was added, and cells were cultured for another 24 hours. Dual-luciferase assay was performed to measure relative luciferase activity (RLA), calculated as the ratio of firefly to Renilla luciferase activity [1]
- AMPK kinase activity assay: C2C12 myotubes were treated with ZLN005 (5–20 μM) for 24 hours. Cell lysates were prepared, and AMPK was immunoprecipitated with AMPK α-subunit antibody. The immunocomplex was incubated with recombinant ACC substrate and ATP in kinase buffer at 30°C for 30 minutes. Phosphorylated ACC (Ser79) was detected by Western blot, and kinase activity was quantified by densitometry [1] |
| Cell Assay |
Western Blot Analysis[1]
Cell Types: L6 myotubes Tested Concentrations: 2.5, 5, 10, 20 μM Incubation Duration: 24 hrs (hours) Experimental Results: Dose-dependent activation of AMPK. HepG2 cell gene expression and lipid metabolism assay: HepG2 cells were seeded in 6-well plates and treated with ZLN005 (5–20 μM) for 24 hours. Total RNA was extracted, reverse-transcribed to cDNA, and RT-PCR was performed to quantify PGC-1α and target gene mRNA levels. For triglyceride measurement, cells were lysed, and triglyceride content was determined by a colorimetric assay kit. Fatty acid oxidation was assessed by incubating cells with [14C]-palmitate for 4 hours, followed by measuring 14CO2 production [1] - C2C12 myotube glucose uptake assay: C2C12 myoblasts were differentiated into myotubes over 7 days. Myotubes were serum-starved for 4 hours, treated with ZLN005 (5–20 μM) for 24 hours, then incubated with 2-NBDG for 30 minutes. Fluorescence intensity was measured by flow cytometry to quantify glucose uptake. Western blot was performed to detect GLUT4 and phospho-AMPK levels [1] - Cell viability assay: HepG2 and C2C12 cells were seeded in 96-well plates, treated with ZLN005 (1–20 μM) for 24 hours, and cell viability was assessed by CCK-8 assay [1] |
| Animal Protocol |
Animal/Disease Models: Eightweeks old db/db mice[1]
Doses: 15 mg/kg Route of Administration: Oral administration; per day for 4 weeks Experimental Results: Random blood glucose and fasting blood glucose levels diminished Dramatically over 4 weeks compared with lean mice . Diabetic db/db mouse model: 8-week-old male db/db mice and age-matched C57BL/6J control mice were used. ZLN005 was dissolved in 0.5% carboxymethylcellulose sodium (CMC-Na) to prepare a suspension. db/db mice were randomly divided into control (vehicle) and treatment groups (n=8/group). The treatment group received ZLN005 by oral gavage at 30 mg/kg/day for 4 weeks, while the control group received 0.5% CMC-Na. Body weight, food intake, and fasting blood glucose were measured weekly. GTT and ITT were performed at the end of week 3. After 4 weeks, mice were sacrificed, and liver, skeletal muscle, and adipose tissues were collected for biochemical and molecular analysis [1] |
| ADME/Pharmacokinetics |
The oral bioavailability of ZLN005 in mice after a single oral administration of 30 mg/kg was approximately 38% [1]
- After oral administration of 30 mg/kg ZLN005 to mice, the peak plasma concentration (Cmax) was 1.8 μg/mL, and the time to peak concentration was 1.2 hours (Tmax) [1] - After intravenous injection of 10 mg/kg ZLN005 to mice, the plasma elimination half-life (t1/2) was approximately 4.5 hours [1] - ZLN005 is widely distributed in various tissues. Two hours after oral administration, the concentrations in the liver (8.6 μg/g), skeletal muscle (6.2 μg/g), and adipose tissue (5.8 μg/g) were relatively high [1] |
| Toxicity/Toxicokinetics |
In vitro toxicity: ZLN005 (1–20 μM) had no effect on the viability of HepG2, C2C12 cells or normal human hepatocytes (LO2), and cell viability remained above 90% at all tested concentrations [1]
- In vivo toxicity: After oral administration of ZLN005 (30 mg/kg/day for 4 weeks) to db/db mice, there were no significant changes in body weight, serum ALT, AST, creatinine or urea nitrogen levels. No obvious adverse reactions (e.g., drowsiness, diarrhea, organ damage) were observed [1] - The plasma protein binding rate of ZLN005 in mouse plasma was approximately 78% as determined by balanced dialysis [1] |
| References | |
| Additional Infomation |
ZLN005 is a novel small-molecule PGC-1α transcriptional regulator, discovered through high-throughput screening of compounds that activate PGC-1α reactive reporter genes [1]. Its core mechanism of action is to directly activate PGC-1α transcription, thereby coordinating the expression of genes involved in glucose metabolism, fatty acid oxidation, and energy homeostasis [1]. ZLN005 has beneficial effects on type 2 diabetes by improving insulin sensitivity, reducing hepatic steatosis, and enhancing energy expenditure, and has no obvious toxicity [1]. It promotes glucose uptake through PGC-1α-dependent and AMPK-dependent pathways in skeletal muscle [1]. ZLN005 shows potential therapeutic value in the treatment of type 2 diabetes and metabolic syndrome [1].
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| Molecular Formula |
C17H18N2
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| Molecular Weight |
250.34
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| Exact Mass |
250.147
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| Elemental Analysis |
C, 81.56; H, 7.25; N, 11.19
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| CAS # |
49671-76-3
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| Related CAS # |
ZLN005-d4;2410443-42-2;ZLN005-d4 hydrochloride
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| PubChem CID |
899323
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| Appearance |
white to off-white solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
415.3±38.0 °C at 760 mmHg
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| Melting Point |
257-258℃
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| Flash Point |
205.4±13.2 °C
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| Vapour Pressure |
0.0±1.0 mmHg at 25°C
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| Index of Refraction |
1.618
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| LogP |
4.93
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
1
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
19
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| Complexity |
299
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1([H])C2=C([H])C([H])=C([H])C([H])=C2N=C1C1C([H])=C([H])C(=C([H])C=1[H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
LQUNNCQSFFKSSK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H18N2/c1-17(2,3)13-10-8-12(9-11-13)16-18-14-6-4-5-7-15(14)19-16/h4-11H,1-3H3,(H,18,19)
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| Chemical Name |
2-(4-(tert-butyl)phenyl)-1H-benzo[d]imidazole
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.2 mg/mL (8.79 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 22.0 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: ≥ 1.25 mg/mL (4.99 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 12.5 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: ≥ 1.25 mg/mL (4.99 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: 1.67 mg/mL (6.67 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.9946 mL | 19.9728 mL | 39.9457 mL | |
| 5 mM | 0.7989 mL | 3.9946 mL | 7.9891 mL | |
| 10 mM | 0.3995 mL | 1.9973 mL | 3.9946 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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