Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson’s diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.

中文翻译：

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2-（6-（5-氯-2-甲氧基苯基）-4-氧代-2-硫代氧代3,4-二氢嘧啶-1（2 H）-基）乙酰胺（PF-06282999）的发现：高度选择性的机制基的髓过氧化物酶抑制剂治疗心血管疾病

髓过氧化物酶（MPO）是一种血红素过氧化物酶，可催化次氯酸的产生。临床证据表明，MPO在各种自身免疫和炎性疾病（包括血管炎，心血管疾病和帕金森氏病）中具有因果作用，这表明MPO抑制剂可能代表了治疗选择。本文中，我们介绍了N -1取代的6-芳基硫尿嘧啶作为MPO的有效抑制剂和选择性抑制剂的设计，合成和临床前评价。抑制作用是通过时间依赖性的方式通过共价不可逆的机制进行的，该机制依赖于MPO催化，与基于机制的失活相一致。ñ与甲状腺过氧化物酶和细胞色素P450同工型相比，1-取代的6-芳基硫尿嘧啶对MPO的分配率低且选择性高。在脂多糖刺激的人全血中，N 1-取代的6-芳基硫尿嘧啶也显示出MPO活性的抑制作用。铅化合物2-（6-（5-氯-2-甲氧基苯基）-4-氧代-2-硫代氧代-3,4-二氢嘧啶-1（2 H）-基）乙酰胺证明了对血浆MPO活性的强烈抑制作用。（PF-06282999，8）口服给药时，以脂多糖处理的猕猴。基于其药理和药代动力学特征，PF-06282999已被推进到人体内药代动力学和安全性研究中。