Biochem/physiol Actions

PF-06282999 is an orally active thiouracil class myeloperoxidase (MPO) suicide substrate (k_inact/K_I = 11600 M^-1s^-1) that targets MPO heme group for mechanism-based irreversible inactivation wtih high selectivity over thyroid peroxidase (TPO k_inact/K_I ﹤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).

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