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CAS No.: 1435467-37-0

PF-06282999 Catalog No. CSN19122

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

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实验方案

技术信息

生物活性

描述The hemoprotein myeloperoxidase (MPO) is one of the major neutrophil bactericidal proteins produced in the bone marrow. PF-06282999 is a thiouracil derivative that acts as an irreversible inactivator of MPO. The blood/plasma ratios for PF-06282999 in mice, rats, dogs, monkeys, and humans are 1.1, 1.1, 0.91, 1.2, and 0.94 respectively^[3]. In the preclinical pharmacokinetics analysis, PF-06282999 showed low CL_p in mice (10.1mL/min/kg), dogs (3.39mL/min/kg), monkeys (10.3mL/min/kg) and moderate CL_p in rats (41.8mL/min/kg). The mean plasma free fraction of PF-06282999 (2 μM) in mouse, rat, dog, monkey, and human was 0.451, 0.447, 0.460, 0.536, and 0.376, respectively. In a cynomolgus monkey LPS challenge study, the EC₅₀ value for PF-06282999 concentration in plasma was 3.8 μM. PF-06282999 also showed an IC50 value of 1.9 μM in the human whole blood assay.^[4].
作用机制PF-06282999 is an irreversible inactivator of MPO. The mechanism underlying the inhibition of MPO by PF-06282999 probably involves the oxidation of the thiouracil sulfur atom in PF-06282999 by oxidized MPO, yielding a thiyl radical that covalently attaches to the heme moiety and ultimately leading to MPO inactivation^[3].
临床研究

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT01965600	Healthy	Phase 1	Terminated	-	United States, North Carolina ... more >> (Drug Shipment Address ONLY) Duke University Health Systems (DUHS) Investigational Drug Services Durham, North Carolina, United States, 27710 Duke Clinical Research Unit Durham, North Carolina, United States, 27710 Collapse <<
NCT01707082	Healthy	Phase 1	Completed	-	Belgium ... more >> Pfizer Investigational Site Brussels, Belgium, B-1070 Collapse <<
NCT01626976	Healthy	Phase 1	Completed	-	Belgium ... more >> Pfizer Investigational Site Bruxelles, Belgium, B-1070 Collapse <<

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参考文献

[1] Dong JQ, Varma MV, 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, Buckbinder L, 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. 2015 Nov 12;58(21):8513-28.
[3] Dong JQ, Varma MV, Wolford A, 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;44(2):209‐219. doi:10.1124/dmd.115.067868
[4] Ruggeri RB, Buckbinder L, Bagley SW, 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. 2015;58(21):8513‐8528. doi:10.1021/acs.jmedchem.5b00963

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 3.0696 mL
- 15.3482 mL
- 30.6964 mL
- 5 mM
- 0.6139 mL
- 3.0696 mL
- 6.1393 mL
- 10 mM
- 0.3070 mL
- 1.5348 mL
- 3.0696 mL

技术信息

CAS号

1435467-37-0

储存条件

粉末: Sealed in dry,Room Temperature

液体: -20°C:3-6 月 -80°C:12月

分子式

C13H12ClN3O3S

运输

蓝冰

分子量

325.77

别名

溶解度

DMSO	64.0 mg/mL (196.5 mM)
Water	Insoluble
Ethanol	Insoluble

动物实验配方

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