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| Targets |
GNF-2133 hydrochloride targets dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a serine/threonine kinase that phosphorylates multiple substrates involved in cell proliferation, differentiation, and survival. DYRK1A has been implicated in the regulation of beta cell proliferation and insulin secretion. By inhibiting DYRK1A with high potency (IC50 = 0.0062 μM), GNF-2133 promotes beta cell proliferation and improves glucose disposal. The compound is highly selective for DYRK1A over GSK3β (>50 μM).
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| ln Vitro |
In vitro, GNF-2133 hydrochloride inhibits DYRK1A with an IC50 of 0.0062 μM and shows >50 μM for GSK3β, demonstrating excellent selectivity. It shows good proliferative capacity and efficacy in rat and human primary beta cells. The compound significantly improves glucose disposal capacity and increases insulin secretion. These properties make it a valuable tool for studying beta cell biology and diabetes.
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| ln Vivo |
GNF2133 hydrochloride (30 mg/kg; po) is well absorbed orally, with an oral bioavailability of 22.3% [1]. GNF2133 hydrochloride (30 mg/kg; oral; once daily for 5 days) has been proven to proliferate beta cells in vivo [1]. GNF2133 hydrochloride (3, 10, 30 mg/kg) significantly enhanced the glucose processing capacity and boosted insulin secretion in RIP-DTA mice [1]. Pharmacokinetic characteristics of GNF2133 hydrochloride in CD-1 mice [1]. Plasma (iv) Plasma (po) Pancreas (po) CL (mL/min/kg) 23.5 // Vss (L/kg) 11 // AUC (h·nM) 3268 10974 144420 Cmax(nM) 1977 1675 13319 tmax< (h) 0.03 3.0 3.0 Clast(nM) 36.6 19 1324 t1/2<(h) 6.6 3.4 6.6 F (%) / 22.3 / CD-1 mouse; 30 mg/kg; Bao[1].
In vivo, GNF-2133 hydrochloride shows good oral absorption and moderate plasma exposure with an oral bioavailability of 22.3%. It significantly improves glucose disposal capacity and increases insulin secretion, supporting its potential for studying type 1 diabetes. The compound's ability to promote beta cell proliferation and improve glucose metabolism makes it a promising tool for diabetes research. However, specific in vivo efficacy data in disease models have not been detailed in the available literature. |
| Enzyme Assay |
For in vitro kinase assays, recombinant DYRK1A protein is incubated with a peptide substrate and ATP in kinase assay buffer. The test compound is added at various concentrations (0.001-1000 nM). Kinase activity is measured using radioactive ATP incorporation or luminescent ADP detection assays. IC50 values are calculated by fitting dose-response curves. Selectivity for DYRK1A over GSK3β is assessed using similar assays with recombinant GSK3β protein.
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| Cell Assay |
For cell-based assays, rat and human primary beta cells or beta cell lines are treated with GNF-2133 hydrochloride at concentrations ranging from 0.01-10 µM. Beta cell proliferation is assessed by measuring cell number or by BrdU or EdU incorporation. Insulin secretion is measured by ELISA in response to glucose stimulation. Glucose uptake and metabolism can also be assessed.
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| Animal Protocol |
Animal/Disease Models: CD-1 mice [1]
Doses: 30 mg/kg Route of Administration: Po Experimental Results: Good oral absorption, moderate plasma exposure, and oral bioavailability of 22.3%. Animal/Disease Models: Wistar Han rat[1] Doses: 30 mg/kg (0.5% methylcellulose + Tween-80) Route of Administration: Po; one time/day for 5 days Experimental Results: Cyclin D1 levels and overall cells Density increased, as did cell proliferation markers Ki67 and insulin. Animal/Disease Models: diphtheria toxin A (RIP-DTA) mice [1] Doses: 3, 10, 30 mg/kg (20 mg/kg doxycycline (Dox) for 5 days) Route of Administration: Po, daily Once, for 35 days Experimental Results: Dramatically improved glucose handling and increased insulin secretion. For in vivo studies, animal models of diabetes (such as streptozotocin-induced diabetic mice or NOD mice) would be used. GNF-2133 hydrochloride would be administered orally at doses determined from pharmacokinetic studies. Blood glucose levels, insulin levels, and glucose tolerance would be assessed. Beta cell mass and proliferation in pancreatic islets would be evaluated by histology and immunohistochemistry. |
| ADME/Pharmacokinetics |
GNF-2133 hydrochloride is orally active and shows good oral absorption with a bioavailability of 22.3%. The compound is soluble in DMSO. Storage is recommended at -20°C for long-term stability. Further detailed PK parameters including half-life, Cmax, and AUC would be available from the primary literature. The compound's molecular weight of 470.99 suggests potential for drug-like properties.
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| Toxicity/Toxicokinetics |
Toxicological data for GNF-2133 hydrochloride have not been extensively reported. As a research compound, it is intended for laboratory use only and is not for human or veterinary use. Standard safety precautions should be followed when handling this compound. Comprehensive toxicology studies would be required before any clinical development.
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| References | |
| Additional Infomation |
GNF-2133 hydrochloride is a potent, selective, orally active DYRK1A inhibitor with IC50 of 0.0062 μM for DYRK1A and >50 μM for GSK3β. It promotes beta cell proliferation and improves glucose disposal and insulin secretion. GNF-2133 hydrochloride has potential for studying type 1 diabetes. It is a research tool and is not approved for clinical use.
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| Molecular Formula |
C24H31CLN6O2
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|---|---|
| Molecular Weight |
470.994943857193
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| Exact Mass |
434.24
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| Elemental Analysis |
C, 61.20; H, 6.63; Cl, 7.53; N, 17.84; O, 6.79
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| CAS # |
2561414-57-9
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| Related CAS # |
GNF2133;2561414-56-8
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| PubChem CID |
156015235
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| Appearance |
Solid powder
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| LogP |
0
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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 |
4
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| Heavy Atom Count |
33
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| Complexity |
622
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.O1CCC(CC1)N1C=C(C2C=CN=C(C=2)NC(N2CCN(CC)CC2)=O)C2C=CN=CC1=2
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| InChi Key |
PKSHRWPMQDLRRB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H30N6O2.ClH/c1-2-28-9-11-29(12-10-28)24(31)27-23-15-18(3-8-26-23)21-17-30(19-5-13-32-14-6-19)22-16-25-7-4-20(21)22;/h3-4,7-8,15-17,19H,2,5-6,9-14H2,1H3,(H,26,27,31);1H
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| Chemical Name |
4-ethyl-N-[4-[1-(oxan-4-yl)pyrrolo[2,3-c]pyridin-3-yl]pyridin-2-yl]piperazine-1-carboxamide;hydrochloride
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| Synonyms |
GNF2133 HCl; GNF2133 hydrochloride; GNF2133; GNF-2133; GNF 2133;
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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 | 2.1232 mL | 10.6159 mL | 21.2319 mL | |
| 5 mM | 0.4246 mL | 2.1232 mL | 4.2464 mL | |
| 10 mM | 0.2123 mL | 1.0616 mL | 2.1232 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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