Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.

髓过氧化物酶（MPO）是在嗜中性粒细胞，单核细胞和巨噬细胞中发现的血红素过氧化物酶，可有效催化内源性氯化物氧化成次氯酸，从而具有抗微生物活性。慢性MPO激活可导致不加区别的蛋白质修饰，从而引起组织损伤，并与慢性炎症性疾病，动脉粥样硬化和急性心血管事件相关。三唑并嘧啶5是可逆的MPO抑制剂；但是，它在酸中的稳定性较差，并且是DNA修复蛋白甲基鸟嘌呤甲基转移酶（MGMT）的不可逆抑制剂。基于结构的药物设计被用于发现具有改进的MPO效力以及酸稳定性，与MGMT无反应性和对甲状腺过氧化物酶（TPO）选择性的苄基三唑并吡啶。本文描述了结构-活性关系，MPO-抑制剂复合物的晶体结构以及急性体内药效学数据。