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].
搜索
