Myeloperoxidase (MPO) is a heme peroxidasethat catalyzes the productionof hypochlorous acid. Clinical evidence suggests a causal role forMPO in various autoimmune and inflammatory disorders including vasculitisand cardiovascular and Parkinson’s diseases, implying thatMPO inhibitors may represent a therapeutic treatment option. Herein,we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selectiveinhibitors of MPO. Inhibition proceeded in a time-dependent mannerby a covalent, irreversible mechanism, which was dependent upon MPOcatalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios andhigh selectivity for MPO over thyroid peroxidase and cytochrome P450isoforms. N1-Substituted-6-arylthiouracils also demonstratedinhibition of MPO activity in lipopolysaccharide-stimulated humanwhole blood. Robust inhibition of plasma MPO activity was demonstratedwith the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oraladministration to lipopolysaccharide-treated cynomolgus monkeys. Onthe basis of its pharmacological and pharmacokinetic profile, PF-06282999has been advanced to first-in-human pharmacokinetic and safety studies. [ABSTRACT FROM AUTHOR]