Basic information Safety Supplier Related

PF-06282999

Basic information Safety Supplier Related

PF-06282999 Basic information

Product Name:
PF-06282999
Synonyms:
  • PF-06282999
  • PF-06282999 (Free base)
  • 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide
  • CS-2543
  • PF-06282999;PF 06282999;PF06282999
  • 1(2H)-Pyrimidineacetamide, 6-(5-chloro-2-methoxyphenyl)-3,4-dihydro-4-oxo-2-thioxo-
  • PF-06282999 >=98% (HPLC)
  • PF06282999,Glutathione Peroxidase,PF 06282999,PF-06282999,Inhibitor,inhibit
CAS:
1435467-37-0
MF:
C13H12ClN3O3S
MW:
325.77
Mol File:
1435467-37-0.mol
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PF-06282999 Chemical Properties

Density 
1.52±0.1 g/cm3(Predicted)
storage temp. 
room temp
solubility 
DMSO:30.0(Max Conc. mg/mL);92.1(Max Conc. mM)
form 
powder
pka
6.85±0.40(Predicted)
color 
white to beige
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PF-06282999 Usage And Synthesis

Uses

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

Biological Activity

PF-06282999 is an orally active thiouracil class myeloperoxidase (MPO) suicide substrate (kinact/KI = 11600 M-1s-1) th at targets MPO heme group for mechanism-based irreversible inactivation wtih high selectivity over thyroid peroxidase (TPO kinact/KI <3 M-1s-1) and heme-containing cytochrome P450 (CYP) isoforms (IC50 >100 μM). PF-06282999 effectively inhibits MPO activity in human blood stimulated by LPS ex vivo (IC50 = 1.9 μM) and in blood of LPS-treated cynomolgus monkeys in vivo (5-80 mg/kg p.o. 1hr post LPS i.v.) with good pharmacokinetics and oral availability (100%/86%/75%/76% in mice/rats/dogs/monkeys). PF-06282999 also exhibits weak PXR activating activity (EC50/Emax = 279 μM/9.36-fold vs.0.8 μM/19.6-fold with rifampin).

in vivo

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. DOI:10.1124/dmd.115.067868
[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 DOI:10.1021/acs.jmedchem.5b00963

PF-06282999Supplier

Adamas Reagent, Ltd.
Tel
400-6009262 16621234537
Email
chenyj@titansci.com
Shanghai Lollane Biological Technology Co.,Ltd.
Tel
021-52996696，15000506266 15000506266
Shanghai EFE Biological Technology Co., Ltd.
Tel
021-65675885 18964387627
Email
info@efebio.com
Shanghai YuanYe Biotechnology Co., Ltd.
Tel
021-61312847; 18021002903
Email
3008007409@qq.com
Tianjin Kailiqi Biotechnology Co., Ltd.
Tel
15076683720
Email
klq@cw-bio.com
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