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| Targets |
Vutiglabridin targets paraoxonase 2 (PON2), a mitochondrial enzyme. It binds to PON2 and restores mitochondrial function. The compound modulates PON2 activity, which is involved in oxidative stress and mitochondrial dysfunction. In Parkinson's disease models, Vutiglabridin targets mitochondrial PON2 and ameliorates neurodegeneration. The compound also modulates PON1 in obesity models. Its anti-obesity effects are mediated through weight loss and normalization of obesity-related parameters. The compound penetrates the brain, allowing it to exert effects in the central nervous system.
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| ln Vitro |
In vitro studies have demonstrated that Vutiglabridin binds to PON2 and restores 1-methyl-4-phenylpyridine (MPP+)-induced neuroblastoma in SH-SY5Y cells. The compound significantly attenuates MPP+-induced neurotoxicity in neuronal cell models. As a racemic compound, its stereoselective pharmacokinetics have been characterized. The compound's anti-obesity activity has been evaluated in cell-based assays measuring adipocyte differentiation and lipid accumulation. Its chemical stability and superior weight loss efficacy compared to glabridin have been confirmed in various in vitro systems.
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| ln Vivo |
In mice fed a high-fat diet, vitigalabridin (HSG4112) completely reverses obesity in a dose-dependent manner. In obese mice generated by high-fat diet (HFD), vetiglabridin (given orally at 10, 30, or 100 mg/kg dose for 6 weeks) decreases body weight in a dose-dependent manner and returns obesity-related parameters to normal[2].
In vivo studies have demonstrated that Vutiglabridin completely reverses obesity in a dose-dependent manner in mice fed a high-fat diet. In high-fat diet (HFD)-induced obese mice, oral administration of Vutiglabridin at 10, 30, or 100 mg/kg for 6 weeks decreases body weight in a dose-dependent manner. The compound achieved significant dose-dependent body weight reduction by 4.0 g (8.3%), 10 g (21%), and 19 g (40%), respectively. It fully reverses adiposity in HFD-induced obese mice. In Parkinson's disease mouse models, Vutiglabridin significantly attenuated MPTP-induced dyskinesia and dopaminergic neuronal damage. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for Vutiglabridin involve testing its binding affinity to PON2. Binding affinity is measured using surface plasmon resonance or isothermal titration calorimetry. Enzyme activity assays measure PON2 activity in the presence of varying concentrations of the compound. For anti-obesity activity, adipocyte differentiation and lipid accumulation assays are performed. The compound's antioxidant activity is assessed using cell-free systems such as DPPH radical scavenging assays. All assays are performed with appropriate controls and standardized protocols to ensure reproducibility of results.
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| Cell Assay |
In vitro cell-based assays for Vutiglabridin involve culturing SH-SY5Y neuroblastoma cells to evaluate its neuroprotective effects. Cells are treated with MPP+ to induce neurotoxicity, and the compound's ability to restore cell viability is assessed. For anti-obesity studies, adipocyte cell lines are treated with the compound and lipid accumulation is measured. Cell viability is assessed using MTT or similar colorimetric assays. Mitochondrial function is evaluated by measuring mitochondrial membrane potential and reactive oxygen species levels. All experiments are performed in triplicate with appropriate controls to ensure statistical reliability.
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| Animal Protocol |
Animal/Disease Models: HFD-induced obese male C57BL/6J mice[2]
Doses: 10, 30, and 100 mg/kg Route of Administration: Orally administered for 6 weeks Experimental Results: Led to significant dose-dependent body weight reduction by 4.0 g (8.3%), 10 g (21%), and 19 g (40%), respectively, compared to the 48.1 g body weight of HFD-induced obese mice administered with only the vehicle at 10, 30, and 100 mg/kg. In vivo animal experiments for Vutiglabridin utilize high-fat diet (HFD)-induced obese male C57BL/6J mice. Animals are administered the compound orally at doses of 10, 30, or 100 mg/kg for 6 weeks. Body weight, food intake, and obesity-related parameters are monitored. For Parkinson's disease studies, mice are treated with MPTP and the compound's ability to attenuate dyskinesia and dopaminergic neuronal damage is assessed. At study termination, blood and tissue samples are collected for biochemical analysis and histopathological examination. Control groups receiving vehicle alone are included for comparison. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of Vutiglabridin reflect its nature as a small molecule. It has a molecular weight of 354.44 and a LogP of 4.6. The compound is soluble in DMSO at 10 mg/mL (28.21 mM). It has one hydrogen bond donor, four hydrogen bond acceptors, and three rotatable bonds. The compound's stereoselective pharmacokinetics have been characterized in species difference studies. It is stored as a powder at -20°C for up to 3 years or at 4°C for 2 years. In solvent, it can be stored at -80°C for 1 year. The compound is stable at ambient temperature for shipping.
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| Toxicity/Toxicokinetics |
The toxicity profile of Vutiglabridin has been evaluated in preclinical studies. The compound has shown a favorable safety profile in animal models. In preclinical efficacy studies, the compound was well-tolerated at doses up to 100 mg/kg. As a clinical phase 2 drug for obesity, it has undergone safety evaluations in human clinical trials. The compound's safety, tolerability, and pharmacokinetics have been studied. However, as with all research compounds, proper handling procedures including use of personal protective equipment are recommended. The compound is intended for research use only and is not for human use.
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| References |
[1]. In Yong Bae, et al. Species Differences in Stereoselective Pharmacokinetics of HSG4112, A New Anti-Obesity Agent. Pharmaceutics. 2020 Feb 3;12(2):127.
[2]. Leo Sungwong Choi, et al. Discovery and preclinical efficacy of HSG4112, a synthetic structural analog of glabridin, for the treatment of obesity. Int J Obes (Lond). 2021 Jan;45(1):130-142. |
| Additional Infomation |
Vutiglabridin (HSG4112, CAS# 1800188-47-9) is a racemic compound and a potent anti-obesity agent. It is an optimized structural analog of glabridin with advantages in weight loss efficacy and chemical stability. The compound is a novel and safe modulator of PON2. Vutiglabridin is a clinical phase 2 drug for the treatment of obesity and has therapeutic effects on mitochondrial PON2 in Parkinson's disease models. The compound penetrates the brain, binds PON2, and restores mitochondrial function. It ameliorates MPTP-induced neurodegeneration in Parkinson's disease mice and fully reverses adiposity in HFD-induced obese mice. The compound is intended for research use only.
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| Molecular Formula |
C22H26O4
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| Molecular Weight |
354.439446926117
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| Exact Mass |
354.183
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| CAS # |
1800188-47-9
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| PubChem CID |
118204185
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| Appearance |
White to off-white solid powder
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| LogP |
4.6
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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 |
3
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| Heavy Atom Count |
26
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| Complexity |
479
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCOC1=CC(=C(C=C1)C2CC3=C(C4=C(C=C3)OC(CC4)(C)C)OC2)O
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| InChi Key |
IUXJXQLTUMGHHL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H26O4/c1-4-24-16-6-7-17(19(23)12-16)15-11-14-5-8-20-18(21(14)25-13-15)9-10-22(2,3)26-20/h5-8,12,15,23H,4,9-11,13H2,1-3H3
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| Chemical Name |
2-(8,8-dimethyl-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]chromen-3-yl)-5-ethoxyphenol
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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 (282.14 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.05 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8214 mL | 14.1068 mL | 28.2135 mL | |
| 5 mM | 0.5643 mL | 2.8214 mL | 5.6427 mL | |
| 10 mM | 0.2821 mL | 1.4107 mL | 2.8214 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.
Link: https://clinicaltrials.gov/ct2/show/NCT06845553
Conditions:Knee Osteoarthritis (Knee OA)Link: https://clinicaltrials.gov/ct2/show/NCT06329141
Conditions:Parkinson DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT05310032
Conditions:Obesity
Title:A Study to Evaluate the Safety and Efficacy of HSG4112 in Overweight and Obese Patients
Status:Completed
updateDate:2024-03-19
Ctid:NCT05197556
Link: https://clinicaltrials.gov/ct2/show/NCT05197556
Conditions:ObesityLink: https://clinicaltrials.gov/ct2/show/NCT04703764
Conditions:ObesityLink: https://clinicaltrials.gov/ct2/show/NCT04732988
Conditions:ObesityLink: https://clinicaltrials.gov/ct2/show/NCT04733001
Conditions:ObesityProducts are for research use only; We do not sell to patients
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