PF-06282999 |
Catalog No.GC19285
One-Click Copy Product Info
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PF-06282999 is a potent and selective myeloperoxidase inhibitor which is potential useful for the treatment of cardiovascular diseases.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1435467-37-0
Sample solution is provided at 25 µL, 10mM.
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PF-06282999 is a potent and selective myeloperoxidase inhibitor which is potential useful for the treatment of cardiovascular diseases.
The estimated EC50 for total 8 concentration in plasma is 3.8 uM, which corresponds well with the IC50 value obtained in the human whole blood assay of 1.9 uM[2].
PF-06282999 is moderately bound to plasma proteins across preclinical species and humans. The blood/plasma ratios for PF-06282999 are 1.1, 1.1, 0.91, 1.2, and 0.94 in mice, rats, dogs, monkeys, and humans, respectively, suggesting that PF-06282999 is equally distributed into plasma and red blood cells[1]. The in vivo pharmacokinetics of PF-06282999 are examined in greater detail in mice, rats, dogs, and monkeys, wherein it is demonstrated to have low CLp in mice (10.1 mL/min/kg), dogs (3.39 mL/min/kg), monkeys (10.3 mL/min/kg) and moderate CLp in rats (41.8 mL/min/kg). The terminal plasma elimination half-lives (t1/2) range from 0.75 to 3.3 h in the four species. Approximately 26-32% of the iv dose of PF-06282999 is excreted in the unchanged form in rat, dog, and monkey urine, wherein it is also shown that it is well distributed with steady state distribution volumes (Vdss) ranging from 0.5-2.1 L/kg in mice, rats, dogs, and monkeys. Following oral administration, PF-06282999 is rapidly (Tmax=0.78-1.70 h) and well absorbed in mice, rats, dogs, and monkeys with oral bioavailability values of 100%, 86%, 75%, and 76%, respectively[2].
References:
[1]. Dong JQ, et al. Pharmacokinetics and Disposition of the Thiouracil Derivative PF-06282999, an Orally Bioavailable, Irreversible Inactivator of Myeloperoxidase Enzyme, Across Animals and Humans. Drug Metab Dispos. 2016 Feb;44(2):209-19.
[2]. Ruggeri RB, et al. Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases. J Med Chem. 20
Kinase experiment: | Test compound is incubated with human whole blood stimulated with bacterial LPS for 4 h, followed by capture of MPO on immobilized anti-MPO antibody coated plates. The captured MPO is washed and residual MPO activity is determined using Amplex Red and H2O2. |
Animal experiment: | In order to ascertain whether the advances noted in the in vitro and ex vivo assays for candidate thiouracil derivatives translated to effective irreversible inhibition of MPO in vivo, PF-06282999 is also advanced to an in vivo pharmacology study in cynomolgus monkeys using iv endotoxin (LPS) challenge, a classic model of inflammatory leukocyte activation with corresponding MPO activation demonstrated in various species including human. In this randomized crossover study, cynomolgus monkeys are orally administered either vehicle or PF-06282999 (5, 20, and 80 mg/kg) 1 h after iv administration of LPS. Blood is sampled throughout the study and heparinized plasma prepared for MPO activity measurements as well as determination of 8 plasma concentrations. Total MPO is captured using anti-MPO antibody coated plates, and following exchange of plasma for drug-free assay media, the residual activity of the captured MPO is measured using the peroxidation of Amplex Red. A mixed effect sigmoid model is applied to study the relationship between plasma exposure of PF-06282999 and the MPO capture activity at 2 h after dose and 3 h after LPS administration, which corresponds to the peak of MPO activity. |
References: [1]. Dong JQ, et al. Pharmacokinetics and Disposition of the Thiouracil Derivative PF-06282999, an Orally Bioavailable, Irreversible Inactivator of Myeloperoxidase Enzyme, Across Animals and Humans. Drug Metab Dispos. 2016 Feb;44(2):209-19. | |
| Cas No. | 1435467-37-0 | SDF | |
| Canonical SMILES | O=C(N)CN(C(C1=CC(Cl)=CC=C1OC)=C2)C(NC2=O)=S | ||
| Formula | C13H12ClN3O3S | M.Wt | 325.77 |
| Solubility | DMSO : ≥ 32 mg/mL (98.23 mM) | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0697 mL | 15.3483 mL | 30.6965 mL |
| 5 mM | 613.9 μL | 3.0697 mL | 6.1393 mL |
| 10 mM | 307 μL | 1.5348 mL | 3.0697 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
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Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL saline, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >99.00% Appearance: A solid
- COA (Certificate of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 34 reference(s) in Google Scholar.)