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| Targets |
Ketohexokinase (KHK, also known as fructokinase). KHK-IN-3 is a highly selective, orally bioavailable dual inhibitor of the human KHK isoforms, KHK-C and KHK-A. KHK is a rate-limiting enzyme and fructokinase involved in fructose metabolism. By inhibiting KHK, the compound reduces fructose metabolism and downstream effects associated with excessive fructose consumption.
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| ln Vitro |
KHK-IN-3 is a ketohexokinase (KHK) inhibitor. It is a highly selective, orally bioavailable dual inhibitor of the human KHK isoforms, KHK-C and KHK-A. By inhibiting KHK, it reduces the phosphorylation of fructose to fructose-1-phosphate (F1P) and decreases ATP consumption. Its specific in vitro activities depend on the concentrations tested and the assay systems used.
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| ln Vivo |
In vivo, KHK-IN-3 is an orally bioavailable KHK inhibitor that can be used in the study of kidney disease, nonalcoholic steatohepatitis (NASH), diabetes, and heart failure. By inhibiting KHK, it reduces fructose metabolism and may ameliorate metabolic disorders associated with excessive fructose consumption. Its oral bioavailability makes it suitable for in vivo administration.
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| Enzyme Assay |
Non-cell-based assays for KHK-IN-3 include KHK enzyme inhibition assays using purified human KHK isoforms. The enzyme is incubated with fructose and ATP in the presence of various concentrations of the compound, and KHK activity is measured by detecting the production of fructose-1-phosphate or ADP. The IC₅₀ values for KHK-C and KHK-A are determined from dose-response curves.
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| Cell Assay |
Cell-based assays for KHK-IN-3 use cells expressing KHK to assess inhibition of fructose metabolism. Cells are treated with the compound and fructose, and fructose-1-phosphate levels are measured by HPLC or LC-MS. The compound's effects on ATP levels, glycolysis, and lipid metabolism can be assessed. Cytotoxicity is assessed using standard cell viability assays.
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| Animal Protocol |
In vivo studies of KHK-IN-3 are conducted in animal models of kidney disease, NASH, diabetes, and heart failure. The compound is administered orally. Fructose metabolism, ATP levels, lipid accumulation, inflammatory markers, and organ function are assessed. Pharmacokinetic parameters are determined from blood samples. The compound's therapeutic potential in fructose-related metabolic disorders is evaluated.
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| ADME/Pharmacokinetics |
KHK-IN-3 has a molecular formula of C₁₈H₂₂F₃N₇O and a molecular weight of 409.41 g/mol. It appears as an off-white to yellow solid powder. It has a LogP of 1.1. Storage: powder at -20°C for 3 years or 4°C for 2 years; in solvent at -80°C for 6 months or -20°C for 1 month. It is an orally bioavailable KHK inhibitor.
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| Toxicity/Toxicokinetics |
Specific toxicity data for KHK-IN-3 are limited. As an investigational compound, its safety profile is being evaluated in preclinical studies. It is intended for research use only and is not for human therapeutic applications. Standard laboratory safety practices should be followed when handling this compound.
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| References | |
| Additional Infomation |
KHK-IN-3 (LY3522348) is a highly selective, orally bioavailable dual inhibitor of the human ketohexokinase (KHK) isoforms, KHK-C and KHK-A. KHK is a rate-limiting enzyme and fructokinase involved in fructose metabolism. KHK-IN-3 can be used in the study of kidney disease, nonalcoholic steatohepatitis (NASH), diabetes, and heart failure. It is for research use only.
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| Molecular Formula |
C18H22F3N7O
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| Molecular Weight |
409.408792972565
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| Exact Mass |
409.183
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| CAS # |
2568608-48-8
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| PubChem CID |
155385439
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| Appearance |
Off-white to yellow solid powder
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| LogP |
1.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
586
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@H]1CCN1C2=NC(=CC(=N2)C(F)(F)F)C3=CN(N=C3)CC(=O)N4CCNCC4
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| InChi Key |
HAUDFIFEGDNKJX-LBPRGKRZSA-N
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| InChi Code |
InChI=1S/C18H22F3N7O/c1-12-2-5-28(12)17-24-14(8-15(25-17)18(19,20)21)13-9-23-27(10-13)11-16(29)26-6-3-22-4-7-26/h8-10,12,22H,2-7,11H2,1H3/t12-/m0/s1
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| Chemical Name |
2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-1-yl]-1-piperazin-1-ylethanone
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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 (~244.3 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.11 mM) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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: 2.5 mg/mL (6.11 mM) 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; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well. 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 3: 2.5 mg/mL (6.11 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4425 mL | 12.2127 mL | 24.4254 mL | |
| 5 mM | 0.4885 mL | 2.4425 mL | 4.8851 mL | |
| 10 mM | 0.2443 mL | 1.2213 mL | 2.4425 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/NCT04559568
Conditions:HealthyProducts are for research use only; We do not sell to patients
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