PF-06282999

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Chemical Structure| 1435467-37-0 同义名 : -
CAS号 : 1435467-37-0
货号 : A443096
分子式 : C13H12ClN3O3S
纯度 : 99%+
分子量 : 325.77
MDL号 : MFCD30533689
存储条件：

Pure form Sealed in dry,2-8°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(322.31 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
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 CLp in mice (10.1mL/min/kg), dogs (3.39mL/min/kg), monkeys (10.3mL/min/kg) and moderate CLp 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].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

3.07mL

0.61mL

0.31mL

15.35mL

3.07mL

1.53mL

30.70mL

6.14mL

3.07mL
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