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Metabolism Glutathione Peroxidase PF06282999

PF06282999

Catalog No. T4090   CAS 1435467-37-0
Synonyms: PF 06282999, PF-06282999

PF-06282999 is a potent and selective myeloperoxidase inhibitor which is potentially useful for the treatment of cardiovascular diseases.

PF06282999, CAS 1435467-37-0
Pack Size Availability Price/USD Quantity
1 mg In Stock 101.00
2 mg In Stock 182.00
5 mg In stock 360.00
10 mg In stock 560.00
25 mg In stock 1150.00
50 mg In stock 1617.00
100 mg In stock 2265.00
1 mL * 10 mM (in DMSO) In stock 280.00
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Purity 98.28%
Purity 98.00%
Biological Description
Chemical Properties
Storage & Solubility Information
Description PF-06282999 is a potent and selective myeloperoxidase inhibitor which is potentially useful for the treatment of cardiovascular diseases.
Targets&IC50 Myeloperoxidase
In vivo 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. 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. 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.
Animal Research
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.
Kinase Assay 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.
Synonyms PF 06282999 , PF-06282999
Purity 98.28%
Molecular Weight 325.77
Formula C13H12ClN3O3S
CAS No. 1435467-37-0

Storage

0-4℃ for short term (days to weeks), or -20℃ for long term (months).

Solubility Information

DMSO: 32 mg/mL

( < 1 mg/ml refers to the product slightly soluble or insoluble )

Citations

References and Literature
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-062821999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases. J Med Chem. 20

Related compound libraries

This product is contained In the following compound libraries:
Bioactive Compound Library Inhibitor Library Clinical Compound Library Anti-Metabolism Disease Compound Library Anti-Cardiovascular Disease Compound Library Anti-cancer Metabolism Compound Library Anti-aging Compound Library Drug Repurposing Library

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PF06282999 AZD 3241

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