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| Targets |
PF-06835919 specifically targets ketohexokinase (KHK), the enzyme that catalyzes the first step in fructose metabolism. It exhibits isoform-selective inhibition, with reported IC₅₀ values of 8.4–10 nM against the KHK-C isoform and 66–170 nM against the KHK-A isoform. This selectivity is crucial for its mechanism, as it allows for isoform-specific mechanistic studies. It displays high selectivity against other sugar kinases.
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| ln Vitro |
In vitro, PF-06835919 is a highly potent inhibitor of KHK. It has an IC50 of approximately 10 nM against human KHK-C and 170 nM against human KHK-A. This inhibition is significant, as it blocks the conversion of fructose to fructose-1-phosphate, a key step in the metabolic cascade that leads to de novo lipogenesis and other adverse metabolic effects. Its potency and selectivity have been established through a series of enzyme activity assays.
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| ln Vivo |
In vivo, PF-06835919 has been evaluated in preclinical and clinical studies. It is an orally bioavailable compound that has demonstrated efficacy in reducing liver fat. In a Phase 2a clinical trial, it showed a ≥18% reduction in whole liver fat in NAFLD participants, making it a clinically validated KHK inhibitor. Its mechanism involves inhibiting fructose metabolism, thereby reducing the substrate for lipogenesis and improving metabolic parameters.
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| Enzyme Assay |
In vitro enzyme/receptor binding studies for PF-06835919 are conducted using KHK enzyme activity assays. In these assays, the enzyme (KHK-C or KHK-A) is incubated with its substrate (fructose) and ATP in the presence of varying concentrations of the inhibitor. The enzyme's activity is measured by detecting the production of fructose-1-phosphate or the consumption of ATP. The IC50 values (8.4-10 nM for KHK-C and 66-170 nM for KHK-A) are then calculated. This confirms the compound's direct binding and inhibition of the enzyme.
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| Cell Assay |
In vitro cellular assays for PF-06835919 are not detailed in the provided sources, but its activity can be studied in cell-based models of fructose metabolism. Hepatocytes or other cell lines would be treated with the compound and then exposed to fructose. The key readouts would include the inhibition of fructose-1-phosphate production, which would be measured by LC-MS/MS, and the downstream effects on de novo lipogenesis, which could be assessed by measuring triglyceride accumulation. These assays would confirm the compound's mechanism of action in a cellular context.
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| Animal Protocol |
In vivo animal studies for PF-06835919 are not extensively detailed in the provided sources, but the compound has been evaluated in preclinical models of metabolic disease. These studies typically involve administering the compound to animal models (e.g., high-fructose-fed rodents) and measuring endpoints such as liver triglyceride levels, hepatic steatosis, and markers of insulin resistance. The results from these studies supported its advancement into clinical trials.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of PF-06835919 are clinically characterized. It has a molecular weight of 356.34 g/mol and a molecular formula of C₁₆H₁₉F₃N₄O₂. It is an orally bioavailable compound. Its ADME (absorption, distribution, metabolism, and excretion) profile is well-studied, with OAT2/OATP1B1-mediated hepatic uptake and CYP3A4 induction liability identified as key aspects. This information is critical for understanding its pharmacokinetics and potential drug-drug interactions.
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| Toxicity/Toxicokinetics |
Toxicological data for PF-06835919 are primarily derived from clinical studies. As a KHK inhibitor, its safety profile has been evaluated in humans. While specific toxicity data are not detailed in the provided sources, its advancement to Phase 2 trials suggests an acceptable safety and tolerability profile. Its mechanism is well-tolerated, as it targets a specific metabolic pathway. However, comprehensive safety data would be available from clinical trial reports.
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| References | |
| Additional Infomation |
PF-06835919 is a first-in-class KHK inhibitor developed for the treatment of metabolic diseases. It is also known as Ketohexokinase inhibitor 1 and MDK1846. Its CAS number is 2102501-84-6. This compound has been granted a Fast Track designation by the FDA for the treatment of NASH. It serves as a clinically advanced reference standard for researchers studying fructose metabolism and its role in metabolic disorders.
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| Molecular Formula |
C16H19F3N4O2
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|---|---|
| Molecular Weight |
356.342873811722
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| Exact Mass |
356.15
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| Elemental Analysis |
C, 53.93; H, 5.37; F, 15.99; N, 15.72; O, 8.98
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| CAS # |
2102501-84-6
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| Related CAS # |
2102501-84-6;
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| PubChem CID |
129278694
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| Appearance |
Solid powder
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| LogP |
2.4
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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 |
25
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| Complexity |
534
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C[C@H]1CCN1C2=NC(=CC(=N2)N3C[C@@H]4[C@H](C3)C4CC(=O)O)C(F)(F)F
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| InChi Key |
MDUYWDNWFXSMJJ-OFLUOSHYSA-N
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| InChi Code |
InChI=1S/C16H19F3N4O2/c1-8-2-3-23(8)15-20-12(16(17,18)19)5-13(21-15)22-6-10-9(4-14(24)25)11(10)7-22/h5,8-11H,2-4,6-7H2,1H3,(H,24,25)/t8-,9?,10-,11+/m0/s1
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| Chemical Name |
2-[(1R,5S)-3-[2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-6-yl]acetic acid
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| Synonyms |
PF-06835919; PF 06835919; PF06835919; MDK1846; MDK-1846; MDK 1846; ketohexokinase inhibitor; ketohexokinase-In-1
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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 (~280.6 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (7.02 mM) in 5% DMSO + 40% PEG300 + 5% Tween-80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), Suspended solution; with ultrasonication.
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 (7.02 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), Clear solution. 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: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) 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. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (20.8 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. View More
Solubility in Formulation 4: ≥ 2.08 mg/mL (5.84 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. Solubility in Formulation 5: ≥ 2.08 mg/mL (5.84 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 DMSO stock solution (20.8 mg/mL) to 900 μL of corn oil and mix well. Solubility in Formulation 6: 0.5 mg/mL (1.40 mM) (saturation unknown) in 1% DMSO + 99% Saline (add these co-solvents sequentially from left to right, and one by one), Suspended solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8063 mL | 14.0315 mL | 28.0631 mL | |
| 5 mM | 0.5613 mL | 2.8063 mL | 5.6126 mL | |
| 10 mM | 0.2806 mL | 1.4032 mL | 2.8063 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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