| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Targets |
Glucokinase (GK), also known as hexokinase IV, is a key enzyme in glucose metabolism primarily expressed in the liver and pancreatic beta-cells. Glucokinase acts as a glucose sensor, regulating glucose-stimulated insulin secretion in the pancreas and hepatic glucose uptake and glycogen synthesis in the liver. PF-04991532 is a hepatoselective glucokinase activator, meaning it preferentially activates glucokinase in the liver to enhance glucose disposal without stimulating insulin secretion.
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| ln Vitro |
PF-04991532 (the active parent compound) activates human glucokinase with an EC50 of 80 nM and rat glucokinase with an EC50 of 100 nM. The compound demonstrates high selectivity for glucokinase over other hexokinase isoforms. As a hepatoselective activator, it shows preferential distribution to the liver, minimizing systemic exposure and reducing the risk of hypoglycemia. (R)-PF-04991532 is the R-enantiomer of the active compound and is used as a reference standard.
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| ln Vivo |
PF-04991532 has progressed to Phase 2 clinical trials for the treatment of type 2 diabetes. In preclinical studies, PF-04991532 lowers blood glucose in diabetic animal models without increasing plasma insulin levels, consistent with a predominantly hepatic mechanism of action. In Phase 2 clinical trials, PF-04991532 demonstrated glucose-lowering efficacy and a favorable safety profile, with a lower incidence of hypoglycemia compared to traditional glucokinase activators that also target pancreatic beta-cells.
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| Enzyme Assay |
For glucokinase activation assays, recombinant human glucokinase is incubated with varying concentrations of glucose (0.5-50 mM) and the test compound in assay buffer containing ATP, MgCl2, and NAD+. Glucokinase activity is measured by coupling with glucose-6-phosphate dehydrogenase and monitoring NADH formation spectrophotometrically at 340 nm. EC50 values are calculated from dose-response curves. For binding studies, isothermal titration calorimetry (ITC) can be used to measure direct binding.
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| Cell Assay |
For hepatoselectivity assessment, primary human hepatocytes or HepG2 cells are treated with varying concentrations of (R)-PF-04991532 or the racemate for 2-24 hours. Glucose consumption and glycogen synthesis are measured by glucose assay kits and glycogen content assays. Glucose-6-phosphate levels are measured by enzymatic methods. For comparison, insulin secretion assays are performed using INS-1 pancreatic beta-cells or isolated pancreatic islets to confirm lack of insulinotropic activity.
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| Animal Protocol |
Preclinical in vivo efficacy studies are performed in rodent models of type 2 diabetes, including ob/ob mice, db/db mice, and Zucker diabetic fatty (ZDF) rats. Animals are orally dosed with PF-04991532 (doses 1-30 mg/kg) once or twice daily for 2-4 weeks. Blood glucose levels are measured at multiple time points after dosing. Intraperitoneal glucose tolerance tests (IPGTT) are performed to assess glucose homeostasis. Liver and plasma drug concentrations are measured to assess hepatoselectivity. Hepatic glycogen content is determined.
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| ADME/Pharmacokinetics |
PF-04991532 is an orally bioavailable small molecule. In preclinical species, PF-04991532 shows good oral absorption (F% = 40-70%) and moderate plasma clearance. The compound demonstrates hepatoselective distribution with higher liver-to-plasma ratios, which is the key design feature to minimize systemic side effects. The terminal half-life (t1/2) is 4-8 hours in rodents, supporting once- or twice-daily dosing. The compound is metabolized primarily by CYP-mediated oxidation and glucuronidation.
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| Toxicity/Toxicokinetics |
In Phase 2 clinical trials, PF-04991532 was generally well-tolerated with a favorable safety profile. The most common adverse events were mild to moderate gastrointestinal disturbances (nausea, diarrhea). Unlike first-generation glucokinase activators that also activate pancreatic GK, PF-04991532 showed a lower incidence of hypoglycemia due to its hepatoselective mechanism. No significant drug-induced liver injury (DILI) or other serious adverse events were reported in clinical studies based on publicly available information.
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| Additional Infomation |
PF-04991532 was developed by Pfizer as a hepatoselective glucokinase activator for the treatment of type 2 diabetes. The compound completed Phase 2 clinical trials, demonstrating glucose-lowering efficacy and a favorable safety profile. The development of hepatoselective glucokinase activators represents an innovative strategy to reduce the risk of hypoglycemia that limited the clinical utility of earlier GK activators that also target pancreatic beta-cells. (R)-PF-04991532 is the R-enantiomer reference standard used for quality control and analytical purposes. This product is for research use only and is not FDA-approved for human therapy.
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| Molecular Formula |
C18H19F3N4O3
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|---|---|
| Molecular Weight |
396.36
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| Related CAS # |
PF-04991532;1215197-37-7
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| Appearance |
White to off-white solid powder
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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 (~252.30 mM)
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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 | 2.5230 mL | 12.6148 mL | 25.2296 mL | |
| 5 mM | 0.5046 mL | 2.5230 mL | 5.0459 mL | |
| 10 mM | 0.2523 mL | 1.2615 mL | 2.5230 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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