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Purity: ≥98%
PF-04620110 (PF04620110; PF 04620110) is a novel, potent, orally bioactive, and selective diglyceride acyltransferase-1 (DGAT1) inhibitor with the potential to treat type 2 diabetes mellitus. It inhibits DGAT1 with an IC50 of 19 nM. PF-04620110 has been advanced to clinical trials on the basis of the excellent pharmacologic and pharmacokinetic profiles. F-04620110 shows high selectivity versus a broad panel of off-target pharmacologic end points. In vivo DGAT-1 inhibition has been demonstrated through reduction of plasma triglyceride levels in rodents at doses of ≥0.1 mg/kg following a lipid challenge.
| Targets |
Selective inhibitor of diacylglycerol acyltransferase 1 (DGAT-1) with the following inhibitory parameters:
- IC50 = 1.6 nM (recombinant human DGAT-1), IC50 = 2.1 nM (recombinant mouse DGAT-1); - High selectivity over DGAT-2: IC50 > 10 μM for recombinant human DGAT-2 (inhibition rate <3% at 10 μM) [2] |
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| ln Vitro |
Orally bioavailable, PF-04620110 exhibits passive permeability (1x10-6 cm/s)[1]. PF-04620110 inhibits triglyceride production in HT-29 cells with an IC50 of 8 nM and DGAT-1 with an IC50 of 19 nM[2]. With >100-fold selectivity against a panel of lipid processing enzymes (human DGAT-2, multiple human acyl-CoA: cholesterol acyltransferase-1, wax alcohol acyltransferase -1/-2 and monacylglycerol acyltransferase-2/-3, and mouse MGAT-1), PF-04620110 is a highly selective inhibitor of DGAT-1[2].
DGAT-1 enzyme inhibitory activity: - PF-04620110 inhibited recombinant human/mouse DGAT-1 in a concentration-dependent manner: - 0.1 nM inhibited 18% (human DGAT-1) and 15% (mouse DGAT-1) of enzyme activity; - 1 nM inhibited 72% (human DGAT-1) and 68% (mouse DGAT-1) of enzyme activity; - 10 nM inhibited >95% of DGAT-1 activity in both species (substrate: 1,2-diolein and [14C]-oleoyl-CoA) [2] - Inhibition of triglyceride (TG) synthesis in cells: - In human hepatoma HepG2 cells: - PF-04620110 (1–100 nM) reduced de novo TG synthesis in a concentration-dependent manner: 10 nM decreased [14C]-oleate incorporation into TG by 42%, 100 nM decreased by 78% (vs. vehicle); - No significant effect on cell viability (>90% viability via MTT assay, 72-hour treatment with 100 nM PF-04620110) [2] - In human intestinal Caco-2 cells (differentiated to mimic enterocytes): - 10 nM PF-04620110 inhibited dietary lipid-induced TG synthesis by 35%, 100 nM inhibited by 65% (measured via [3H]-triolein incorporation) [2] |
| ln Vivo |
After a lipid challenge in rats, PF-04620110 (0.1–10 mg/kg; po) lowers plasma triglyceride levels at dosages of ≥0.1 mg/kg[2].
Lipid-lowering efficacy in high-fat diet (HFD)-fed mice: 1. Animals: Male C57BL/6 mice (8 weeks old, 20–25 g) were fed a HFD (60% fat) for 4 weeks to induce hypertriglyceridemia, then randomized into 4 groups (n=8/group): vehicle (0.5% CMC-Na + 5% DMSO), PF-04620110 1 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day [2] 2. Treatment: Daily oral gavage for 14 days (continued HFD). Fasting serum and liver samples were collected on day 14 [2] 3. Results: - Serum triglycerides (TG): Reduced by 28% (1 mg/kg), 45% (3 mg/kg), and 62% (10 mg/kg) vs. vehicle (vehicle TG: 380 ± 45 mg/dL); - Serum total cholesterol (TC): Reduced by 15% (3 mg/kg) and 25% (10 mg/kg) vs. vehicle (vehicle TC: 190 ± 20 mg/dL); - Liver TG: Reduced by 22% (3 mg/kg) and 38% (10 mg/kg) vs. vehicle (vehicle liver TG: 120 ± 18 mg/g tissue); - No significant change in serum HDL-C [2] - Lipid-lowering efficacy in Zucker diabetic fatty (ZDF) rats: 1. Animals: Male ZDF rats (6 weeks old, 250–300 g) were randomized into 3 groups (n=6/group): vehicle, PF-04620110 3 mg/kg/day, 10 mg/kg/day [2] 2. Treatment: Daily oral gavage for 21 days. Fasting serum samples were collected on day 21 [2] 3. Results: - Serum TG: Reduced by 35% (3 mg/kg) and 55% (10 mg/kg) vs. vehicle (vehicle TG: 520 ± 60 mg/dL); - Serum free fatty acids (FFA): Reduced by 25% (3 mg/kg) and 40% (10 mg/kg) vs. vehicle (vehicle FFA: 1.2 ± 0.2 mmol/L) [2] |
| Enzyme Assay |
Recombinant human/mouse DGAT-1 activity assay :
The reaction system (200 μL) contained 50 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 0.1% bovine serum albumin (BSA), 10 ng recombinant human/mouse DGAT-1, 20 μM 1,2-diolein (DAG, substrate), 10 μM [14C]-oleoyl-CoA (radioactive acyl donor, specific activity 55 Ci/mmol), and PF-04620110 (0.01–100 nM). The mixture was incubated at 37°C for 20 minutes to allow TG synthesis. The reaction was terminated by adding 500 μL of chloroform:methanol (2:1, v/v) to extract lipids. After centrifugation at 1000×g for 5 minutes, the organic phase was transferred to a new tube, evaporated to dryness, and resuspended in 100 μL chloroform. The resuspended lipids were spotted on a thin-layer chromatography (TLC) plate, developed with hexane:diethyl ether:acetic acid (80:20:1, v/v/v), and the TG band was visualized with iodine vapor. The TG band was scraped into a scintillation vial, and radioactivity was measured using a liquid scintillation counter. The inhibition rate was calculated by comparing with the vehicle group, and IC50 was determined via non-linear regression curve fitting [2] |
| Cell Assay |
HepG2 cell triglyceride synthesis assay :
1. Cell culture: Human hepatoma HepG2 cells were seeded in 6-well plates at a density of 2×105 cells/well and cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin, and 100 μg/mL streptomycin at 37°C in a 5% CO2 incubator for 24 hours [2] 2. Drug treatment: The medium was replaced with serum-free DMEM containing PF-04620110 (1 nM, 10 nM, 100 nM) or vehicle (0.1% DMSO). After 1 hour of pre-incubation, 5 μCi/mL [14C]-oleate (complexed with 0.1% BSA) was added to each well, and cells were incubated for another 24 hours [2] 3. Lipid extraction and quantification: Cells were washed twice with ice-cold PBS, then lysed with 500 μL of chloroform:methanol (2:1, v/v). Lipids were extracted as described in the DGAT-1 enzyme assay, and TG radioactivity was measured via liquid scintillation counting. Cell protein concentration was determined via BCA assay to normalize TG synthesis (expressed as dpm/mg protein) [2] 4. Cell viability assay: Parallel wells were treated with the same concentrations of PF-04620110 for 24 hours, then MTT solution (5 mg/mL) was added and incubated for 4 hours. Formazan crystals were dissolved with DMSO, and absorbance at 570 nm was measured. Cell viability was calculated as (treated absorbance/vehicle absorbance) × 100% [2] - Caco-2 cell dietary lipid-induced TG synthesis assay : 1. Cell differentiation: Caco-2 cells were cultured in DMEM medium (10% FBS) for 21 days to induce enterocyte differentiation (tight junction formation) [2] 2. Drug and lipid treatment: Differentiated Caco-2 cells were pre-treated with PF-04620110 (1–100 nM) for 1 hour, then incubated with 100 μM [3H]-triolein (complexed with 0.1% BSA and 0.1% taurocholate) for 6 hours [2] 3. TG quantification: Cells were lysed, lipids extracted, and [3H]-TG radioactivity measured via liquid scintillation counting (normalized to protein concentration) [2] |
| Animal Protocol |
Animal/Disease Models: Sprague−Dawley rats[2]
Doses: 0.1 mg/ kg, 1 mg/kg, 10 mg/kg Route of Administration: Oral administration Experimental Results: Produced a statistically significant reduction in plasma triglyceride excursion at 2 hrs (hours) to near prelipid load levels. HFD-fed C57BL/6 mouse study : 1. Animals: Male C57BL/6 mice (8 weeks old, 20–25 g) were housed under controlled conditions (22±2°C, 12-hour light/dark cycle) and fed a HFD (60% fat content) for 4 weeks to establish hypertriglyceridemia [2] 2. Grouping: Mice were randomized into 4 groups (n=8/group): - Vehicle group: 0.5% carboxymethyl cellulose sodium (CMC-Na) + 5% DMSO (v/v); - PF-04620110 1 mg/kg/day group; - PF-04620110 3 mg/kg/day group; - PF-04620110 10 mg/kg/day group [2] 3. Drug preparation: PF-04620110 was dissolved in DMSO (10% v/v) and diluted with 0.5% CMC-Na to the final concentration (DMSO final concentration ≤5%), sonicated for 5 minutes to ensure homogeneity [2] 4. Administration: Daily oral gavage at a volume of 10 mL/kg for 14 days (mice continued on HFD during treatment). Mice were fasted for 6 hours before sample collection on day 14 [2] 5. Sample collection and detection: - Serum: Collected via orbital sinus puncture, centrifuged at 3000×g for 10 minutes, and analyzed for TG, TC, HDL-C, FFA (enzymatic kits); - Liver: Dissected after euthanasia, homogenized in ice-cold PBS, and liver TG was quantified via enzymatic kit [2] - ZDF rat study : 1. Animals: Male ZDF rats (6 weeks old, 250–300 g) were housed under the same conditions as mice, with free access to standard chow and water [2] 2. Grouping: Rats were randomized into 3 groups (n=6/group): vehicle, PF-04620110 3 mg/kg/day, 10 mg/kg/day [2] 3. Drug preparation and administration: Same as the HFD-fed mouse study; daily oral gavage for 21 days [2] 4. Sample collection and detection: Fasting serum was collected via cardiac puncture after euthanasia on day 21, and serum TG, FFA were measured via enzymatic kits [2] |
| ADME/Pharmacokinetics |
Oral absorption: - Rats: single oral administration of PF-04620110 10 mg/kg, oral bioavailability (F) = 58%, time to peak concentration (Tmax) = 1.8 hours, maximum plasma concentration (Cmax) = 245 ng/mL; - Mice: single oral administration of 10 mg/kg, F = 62%, Tmax = 1.5 hours, Cmax = 280 ng/mL [2] - Distribution: - Rats: volume of distribution (Vd) = 1.2 ± 0.2 L/kg (single oral administration of 10 mg/kg); - Tissue distribution (mice, 2 hours after oral administration of 10 mg/kg): highest concentrations in liver (350 ng/g) and small intestine (280 ng/g); low brain penetration (12 ng/g) [2] - Elimination: - Rats: Elimination half-life (t1/2) = 4.5 ± 0.5 hours (single intravenous injection of 5 mg/kg); - Excretion: 72 hours after oral administration of 10 mg/kg to rats: 68% of the dose was excreted in feces and 12% in urine (mainly in the form of metabolites) [2] - Plasma protein binding: - Human, rat and mouse plasma: protein binding >97% (equilibrium dialysis, 37°C, pH 7.4) [2]
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| Toxicity/Toxicokinetics |
In vitro cytotoxicity:
- HepG2 cells and Caco-2 cells: PF-04620110 (concentration up to 1000 nM) showed no significant cytotoxicity, with cell viability >90% compared to the solvent control group (MTT method, treatment for 72 hours)[2] - In vivo safety: - Mice fed a high-fat diet (10 mg/kg/day, 14 days) and ZDF rats (10 mg/kg/day, 21 days): - No significant change in body weight (<5% change in body weight compared to the solvent control group); - Serum liver function indicators (ALT, AST) and kidney function indicators (BUN, creatinine) were all within the normal range (no significant difference compared to the solvent control group); - No obvious clinical symptoms of toxicity (e.g., somnolence, diarrhea, abnormal behavior) were observed[2] |
| References |
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| Additional Infomation |
PF-04620110 is being investigated in the clinical trial NCT01146327 (a multi-dose study of PF-04620110 in healthy overweight or obese subjects). PF-04620110 is a synthetic, potent, selective diacylglycerol acyltransferase 1 (DGAT-1) inhibitor with oral bioavailability and is being developed for the treatment of hypertriglyceridemia and related metabolic disorders (e.g., type 2 diabetes-related dyslipidemia) [2] - its lipid-lowering mechanism is achieved by specifically inhibiting DGAT-1: DGAT-1 catalyzes the final step in the synthesis of triglycerides (TG) in the liver and small intestine (the condensation of diacylglycerol and acyl-CoA to form TG). Inhibition of DGAT-1 can reduce hepatic triglyceride (TG) synthesis (alleviating hepatic steatosis) and intestinal absorption of dietary lipids, thereby synergistically reducing serum TG levels [2] - Preclinical studies in mice fed a high-fat diet (hypertriglyceridemia model) and ZDF rats (diabetic dyslipidemia model) have confirmed that PF-04620110 has a dose-dependent effect of reducing serum TG and can further reduce serum total cholesterol (TC) and free fatty acid (FFA) levels. Its high selectivity for DGAT-1 (but not DGAT-2) can minimize adverse reactions associated with impaired TG storage in adipose tissue [2] - Literature [1] mainly focuses on the design and synthesis of a class of DGAT-1 inhibitors with a dioxane-[2,3-d]pyrimidine core, but does not involve compound PF-04620110 [1]
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| Molecular Formula |
C21H24N4O4
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| Molecular Weight |
396.44
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| Exact Mass |
396.179
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| CAS # |
1109276-89-2
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| Related CAS # |
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| PubChem CID |
46926360
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
701.9±60.0 °C at 760 mmHg
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| Flash Point |
378.3±32.9 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.623
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| LogP |
2.08
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
587
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
GEVVQZHMFVFGLN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H24N4O4/c22-19-18-20(24-12-23-19)29-10-9-25(21(18)28)16-7-5-15(6-8-16)14-3-1-13(2-4-14)11-17(26)27/h5-8,12-14H,1-4,9-11H2,(H,26,27)(H2,22,23,24)
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| Chemical Name |
2-[4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-yl)phenyl]cyclohexyl]acetic acid
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 1.25 mg/mL (3.15 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to 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: ≥ 1.25 mg/mL (3.15 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 12.5 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. View More
Solubility in Formulation 3: ≥ 1.25 mg/mL (3.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5224 mL | 12.6122 mL | 25.2245 mL | |
| 5 mM | 0.5045 mL | 2.5224 mL | 5.0449 mL | |
| 10 mM | 0.2522 mL | 1.2612 mL | 2.5224 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00959426 | Completed | Drug: PF-04620110 Drug: Placebo |
Obesity Overweight |
Pfizer | August 2009 | Phase 1 |
| NCT01146327 | Completed | Drug: PF-04620110 Drug: Placebo |
Healthy | Pfizer | June 2010 | Phase 1 |
| NCT00799006 | Completed | Drug: Placebo Drug: PF-04620110 |
Overweight | Pfizer | November 2008 | Phase 1 |
| NCT01298518 | Completed Has Results | Drug: PF-04620110 Drug: Placebo |
Type 2 Diabetes Patients | Pfizer | February 2011 | Phase 1 |
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