PF-06282999 is a potent and selective myeloperoxidase Inhibitor which is potential useful for the Treatment of Cardiovascular Diseases. PF-06282999 displayed excellent oral pharmacokinetics in preclinical species and robust irreversible inhibition of plasma MPO activity both in human blood stimulated exogenously and in plasma collected after oral (po) administration to lipopolysaccharide (LPS)-treated cynomolgus monkeys. PF-06282999 has been advanced into first-in-human pharmacokinetics and safety studies.
CAS Number: 1435467-37-0
Molecular Weight: 325.77
Chemical Name: 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide
Appearance: Solid Power.
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO, not in water
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥360 days if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
PF-06282999 (Compound 8) is a potent and selective myeloperoxidase inhibitor. The estimated EC50 for total PF-06282999 concentration in plasma is 3.8 μM, which corresponds well with the IC50 value obtained in the human whole blood assay of 1.9 μM.
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. 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.
- Ruggeri RB, Buckbinder L, Bagley SW, Carpino PA, Conn EL, Dowling MS, Fernando DP, Jiao W, Kung DW, Orr ST, Qi Y, Rocke BN, Smith A, Warmus JS, Zhang Y, Bowles D, Widlicka DW, Eng H, Ryder T, Sharma R, Wolford A, Okerberg C, Walters K, Maurer TS, Zhang Y, Bonin PD, Spath SN, Xing G, Hepworth D, Ahn K, Kalgutkar AS. 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 Oct 28. [Epubahead of print] PubMed PMID: 26509551.
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