PF-1355是一种基于机制的髓过氧化物酶抑制剂，可预防免疫复合物血管炎和抗肾小球基底膜肾小球肾炎。,Journal of Pharmacology and Experimental Therapeutics

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PF-1355是一种基于机制的髓过氧化物酶抑制剂，可预防免疫复合物血管炎和抗肾小球基底膜肾小球肾炎。
Journal of Pharmacology and Experimental Therapeutics ( IF 3.1 ) Pub Date : 2015-02-24 , DOI: 10.1124/jpet.114.221788
Wei Zheng ₁ , Roscoe Warner ₁ , Roger Ruggeri ₁ , Chunyan Su ₁ , Christian Cortes ₁ , Athanasia Skoura ₁ , Jessica Ward ₁ , Kay Ahn ₁ , Amit Kalgutkar ₁ , Dexue Sun ₁ , Tristan S Maurer ₁ , Paul D Bonin ₁ , Carlin Okerberg ₁ , Walter Bobrowski ₁ , Thomas Kawabe ₁ , Yanwei Zhang ₁ , Timothy Coskran ₁ , Sammy Bell ₁ , Bhupesh Kapoor ₁ , Kent Johnson ₁ , Leonard Buckbinder ₂

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小血管血管炎是危及生命的疾病，患者通常会出现肾脏和肺部损伤。疾病的发病机制与中性粒细胞的积累，活化和氧化损伤有关，后者主要由髓过氧化物酶（MPO）驱动，后者会在其他氧化剂中产生次氯酸。MPO与血管炎，弥散性血管炎症有关，通常涉及肺和肾微脉管系统，并经常导致严重后果。MPO通过以下作用导致血管损伤：1）分解一氧化氮，损害血管舒缩功能；2）对脂蛋白和内皮细胞造成氧化损伤，导致动脉粥样硬化；3）刺激中性粒细胞胞外陷阱的形成，导致血管闭塞和血栓形成。在这里，我们报告了一种基于选择性2-硫尿嘧啶机理的MPO抑制剂（PF-1355 [2-（6-（2,5-二甲氧基苯基）-4-氧代-2-硫代氧-3,4-二氢嘧啶-1（2H）- yl）乙酰胺），并证明MPO在小鼠疾病模型中是血管炎的关键介质。PF-1355暴露与MPO活性相关的药代动力学/药效学响应模型源自小鼠腹膜炎。然后在肺部疾病的免疫复合物模型中检查了MPO活性对血管炎的贡献。口服PF-1355可降低血浆MPO活性，血管水肿，中性粒细胞募集和升高的循环细胞因子。在以前称为Goodpasture疾病的抗肾小球基底膜疾病模型中，PF-1355治疗可完全抑制蛋白尿和慢性肾功能不全。

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PF-1355, a mechanism-based myeloperoxidase inhibitor, prevents immune complex vasculitis and anti-glomerular basement membrane glomerulonephritis.

Small vessel vasculitis is a life-threatening condition and patients typically present with renal and pulmonary injury. Disease pathogenesis is associated with neutrophil accumulation, activation, and oxidative damage, the latter being driven in large part by myeloperoxidase (MPO), which generates hypochlorous acid among other oxidants. MPO has been associated with vasculitis, disseminated vascular inflammation typically involving pulmonary and renal microvasculature and often resulting in critical consequences. MPO contributes to vascular injury by 1) catabolizing nitric oxide, impairing vasomotor function; 2) causing oxidative damage to lipoproteins and endothelial cells, leading to atherosclerosis; and 3) stimulating formation of neutrophil extracellular traps, resulting in vessel occlusion and thrombosis. Here we report a selective 2-thiouracil mechanism-based MPO inhibitor (PF-1355 [2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide) and demonstrate that MPO is a critical mediator of vasculitis in mouse disease models. A pharmacokinetic/pharmacodynamic response model of PF-1355 exposure in relation with MPO activity was derived from mouse peritonitis. The contribution of MPO activity to vasculitis was then examined in an immune complex model of pulmonary disease. Oral administration of PF-1355 reduced plasma MPO activity, vascular edema, neutrophil recruitment, and elevated circulating cytokines. In a model of anti-glomerular basement membrane disease, formerly known as Goodpasture disease, albuminuria and chronic renal dysfunction were completely suppressed by PF-1355 treatment. This study shows that MPO activity is critical in driving immune complex vasculitis and provides confidence in testing the hypothesis that MPO inhibition will provide benefit in treating human vasculitic diseases.

更新日期：2019-11-01

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