PF-04620110DGAT-1 inhibitor,potent and selective CAS# 1109276-89-2 |
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Quality Control & MSDS
3D structure
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| Cas No. | 1109276-89-2 | SDF | Download SDF |
| PubChem ID | 46926360 | Appearance | Powder |
| Formula | C21H24N4O4 | M.Wt | 396.44 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : 12.5 mg/mL (31.53 mM; Need ultrasonic) | ||
| Chemical Name | 2-[4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-yl)phenyl]cyclohexyl]acetic acid | ||
| SMILES | C1CC(CCC1CC(=O)O)C2=CC=C(C=C2)N3CCOC4=NC=NC(=C4C3=O)N | ||
| Standard InChIKey | GEVVQZHMFVFGLN-UHFFFAOYSA-N | ||
| Standard InChI | 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) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | PF-04620110 is a potent and selective inhibitor of DGAT-1 with IC50 value of 19 nM. | |||||
| Targets | DGAT-1 | |||||
| IC50 | 19 nM | |||||
| Kinase experiment [1]: | |
| In Vitro Assay for DGAT-1 Enzyme Inhibition: | Human full-length diacylglycerol:acylCoA acyltransferase 1 (DGAT-1) was expressed in Sf9 insect cells which are then lysed and a crude membrane fraction (105, 000 x g pellet) was prepared. DGAT-1 activity was measured in 384-well format in a total assay volume of 25 μl that contained, Hepes buffer (50 mM, pH7.5), MgCl2 (10 mM), bovine serum albumin (0.6 mg/ml), [14C]decanoylCoA (20 μM, 58 Ci/mol) and membranes (25 μg/ml) into which 1,2 dioleoyl-sn-glycerol (75 μM) in acetone has already been incorporated. Inhibitors in DMSO were pre-incubated with membranes before initiating the DGAT-1 reaction by the addition of decanoylCoA.The reactions were allowed to proceed for 1.5 h at room temperature and then terminated by the addition of 10 μl of HCl (0.5 M). Reaction mixtures were neutralized by the addition of 15 μl of tris(hydroxy-methyl)aminomethane (1M, pH 8.0) and then mixed by trituration with 37.5 μl of Microscint-E . Plates contents were allowed to partition for 15 to 30 min before 14C was measured in a scintillation spectrometer. Percent inhibition of test compounds was computed as 100-(DPM DMSO uninhibited- DPM test compound)/(DPM DMSO uninhibited). |
| Cell experiment [1]: | |
| Cell lines | Human intestinal epithelial cells |
| Preparation method | Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
| Reacting condition | 5 hours at 37oC |
| Applications | PF-04620110 (IC50 39 nM) inhibits the incorporation of 3H-glycerol into TG. |
| Animal experiment [2]: | |
| Animal models | C57BL/6J and B6.129S4-Dgat1tm1Far (DGAT1 knockout mice) male mice (7–12 wk of age) |
| Dosage form | Oral dose of 1, 0.3, 0.1, and 0.01 mg/kg (TG/retinyl palmitate tolerance test) |
| Application | Administration of a single dose of a DGAT1 inhibitor, PF-04620110, reduces postprandial plasma TG and retinyl palmitate excursions in mice. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: 1. Dow RL, Li JC, Pence MP, Gibbs EM, LaPerle JL, Litchfield J, Piotrowski DW, Munchhof MJ, Manion TB, Zavadoski WJ, Walker GS, McPherson RK, Tapley S, Sugarman E, Guzman-Perez A, DaSilva-Jardine P. Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1. ACS Med Chem Lett. 2011 Mar 18;2(5):407-12. 2. Maciejewski BS, LaPerle JL, Chen D, Ghosh A, Zavadoski WJ, McDonald TS, Manion TB, Mather D, Patterson TA, Hanna M, Watkins S, Gibbs EM, Calle RA, Steppan CM. Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans. Am J Physiol Gastrointest Liver Physiol. 2013 Jun 1;304(11):G958-69. | |
PF-04620110 Dilution Calculator
PF-04620110 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.5224 mL | 12.6122 mL | 25.2245 mL | 50.449 mL | 63.0612 mL |
| 5 mM | 0.5045 mL | 2.5224 mL | 5.0449 mL | 10.0898 mL | 12.6122 mL |
| 10 mM | 0.2522 mL | 1.2612 mL | 2.5224 mL | 5.0449 mL | 6.3061 mL |
| 50 mM | 0.0504 mL | 0.2522 mL | 0.5045 mL | 1.009 mL | 1.2612 mL |
| 100 mM | 0.0252 mL | 0.1261 mL | 0.2522 mL | 0.5045 mL | 0.6306 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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PF-04620110 is a potent, selective and orally-bioavailable inhibitor of diacylglycerol acyltransferase 1 (DGAT-1), an enzyme catalyzing the final committed step in the biosynthesis of triglycerides, that inhibits DGAT-1 with values of 50% inhibition concentration IC50 of 19 nM and 8 nM in human and HT-29 cells respectively. PF-04620110 displays a highly selective, more than 100 fold, inhibition against DGAT-1 rather than a range of lipid processing enzymes, including human DGAT-2, human acyl-CoA:cholesterol acyltransferase 1, human acyl-CoA:wax alcohol acyltransferase 1, human acyl-CoA:wax alcohol acyltransferase 2, human acyl-CoA:monacylglycerol acyltransferase 2, human acyl-CoA:monacylglycerol acyltransferase 3 and mouse MGAT 1.
Reference
Lee KR, Choi SH, Song JS, Seo H, Chae YJ, Cho HE, Ahn JH, Ahn SH, Bae MA. Determination of PF-04620110, a novel inhibitor of diacylglycerol acyltransferase-1, in rat plasma using liquid chromatography-tandem mass spectrometry and its application in pharmacokinetic studies. Biomed Chromatogr. 2013; 27(7):846-852.
Robert L. Dow *, Jian-Cheng Li , Michael P. Pence , E. Michael Gibbs , Jennifer L. LaPerle , John Litchfield , David W. Piotrowski , Michael J. Munchhof , Tara B. Manion , William J. Zavadoski , Gregory S. Walker , R. Kirk McPherson , Susan Tapley , Eliot Sugarman , Angel Guzman-Perez , and Paul DaSilva-Jardine Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1. ACS Med. Chem. Lett., 2011, 2 (5), pp 407–412
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Determination of PF-04620110, a novel inhibitor of diacylglycerol acyltransferase-1, in rat plasma using liquid chromatography-tandem mass spectrometry and its application in pharmacokinetic studies.[Pubmed:23420715]
Biomed Chromatogr. 2013 Jul;27(7):846-52.
In this study, we developed a method for the determination of PF-04620110 (2-{(1r,4r)-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl) phenyl]cyclohexyl}acetic acid), a novel diacylglycerol acyltransferase 1 (DGAT-1) inhibitor, in rat plasma and validated it using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rat plasma samples were processed following a protein precipitation method by using acetonitrile and were then injected into an LC-MS/MS system for quantification. PF-04620110 and imipramine (internal standard) were separated using a Hypersil Gold C18 column, with a mixture of acetonitrile and 10 mm ammonium formate (90:10, v/v) as the mobile phase. The ion transitions monitored in positive-ion mode [M + H](+) of multiple-reaction monitoring were m/z 397.0 --> 260.2 for PF-04620110 and m/z 280.8 --> 86.0 for imipramine. The detector response was specific and linear for PF-04620110 at concentrations within the range 0.05-50 microg/mL and the signal-to-noise ratios for the samples were >/=10. The intra- and inter-day precision and accuracy of the method matched the acceptance criteria for assay validation. PF-04620110 was stable under various processing and/or handling conditions. PF-04620110 concentrations in the rat plasma samples could be measured up to 24 h after intravenous or oral administration of PF-04620110, suggesting that the assay is useful for pharmacokinetic studies in rats.
Defining the key pharmacophore elements of PF-04620110: discovery of a potent, orally-active, neutral DGAT-1 inhibitor.[Pubmed:23871442]
Bioorg Med Chem. 2013 Sep 1;21(17):5081-97.
DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures.
Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1.[Pubmed:24900321]
ACS Med Chem Lett. 2011 Mar 18;2(5):407-12.
Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final committed step in the biosynthesis of triglycerides. DGAT-1 knockout mice have been shown to be resistant to diet-induced obesity and have increased insulin sensitivity. Thus, inhibition of DGAT-1 may represent an attractive target for the treatment of obesity or type II diabetes. Herein, we report the discovery and characterization of a potent and selective DGAT-1 inhibitor PF-04620110 (3). Compound 3 inhibits DGAT-1 with an IC50 of 19 nM and 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. On the basis of this pharmacologic and pharmacokinetic profile, compound 3 has been advanced to human clinical studies.
