PF-06282999 is an orally bioavailable thiouracil derivative developed as a selective, mechanism-based inactivator of myeloperoxidase (MPO). The compound is identified by CAS 1435467-37-0 and has the formula C13H12ClN3O3S. Unlike a reversible competitive inhibitor, it must be processed by MPO before it forms the species responsible for irreversible enzyme inactivation.
Its scaffold consists of a 4-oxo-2-thioxopyrimidine ring bearing a 5-chloro-2-methoxyphenyl substituent and an acetamide side chain. The design combines MPO-dependent reactivity with oral exposure and limited inhibition of related heme enzymes.
Application of PF-06282999
The compound is useful for investigating how MPO-derived oxidants contribute to inflammatory tissue injury and vascular disease. It can be applied in enzyme-kinetics assays, LPS-stimulated whole-blood experiments, and animal models of atherosclerosis. Its irreversible action also supports washout studies that separate sustained MPO suppression from free-compound exposure. In plaque models, lesion composition and total plaque burden should be measured independently because they may respond differently.
In Vitro
Studies from the Pfizer PF-06282999 program report a human MPO Ki of approximately 316 nM and a kinact/KI of 11,600 M⁻¹s⁻¹. Activity against thyroid peroxidase was more than 3,800-fold weaker. PF-06282999 showed no meaningful direct inhibition of the tested cytochrome P450 isoforms. Separate studies, however, demonstrated PXR-mediated induction of CYP3A4 expression and activity.
In LPS-stimulated human whole blood, the compound inhibited MPO activity with an IC50 of 1.9 µM. Separate cellular studies later identified activation of human PXR and induction of CYP3A4, an important off-target property to consider in experimental interpretation.
In Vivo
PF-06282999 showed good oral bioavailability across mice, rats, dogs, and cynomolgus monkeys. Oral dosing suppressed plasma MPO activity in LPS-treated monkeys. The parent PF-06282999 molecular structure was resistant to metabolic turnover, with renal excretion of unchanged compound projected as the principal human clearance route.
In Ldlr-deficient mice fed a Western diet, 15 mg/kg twice daily for 14 weeks reduced aortic-root lesion necrotic core area by 37% and increased collagen area as a percentage of lesion area. Total lesion area was unchanged, indicating altered plaque composition rather than regression. A first-in-human study assessed pharmacokinetics and safety in healthy volunteers over a 20–200 mg dose range.
Biochemical and Physiological Actions
MPO uses hydrogen peroxide and chloride to generate hypochlorous acid, a strong oxidant involved in antimicrobial defense but also capable of modifying lipoproteins and vascular tissue during inflammation. The PF-06282999 chemical structure is oxidized within the MPO catalytic cycle and forms a covalent adduct with the heme group. This stops further catalytic turnover, so activity remains suppressed until functional enzyme is replenished.
Features and Benefits of PF-06282999
- Mechanism-based, irreversible MPO inactivation with quantified kinetic efficiency
- High kinetic selectivity over thyroid peroxidase.
- Activity demonstrated in human whole blood and multiple in vivo models.
- Oral exposure documented across preclinical species and healthy volunteers.
- Verified formula C13H12ClN3O3S and PF-06282999 molecular weight of 325.77 g/mol
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