Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-05-12 , DOI: 10.1016/j.bmc.2020.115548 Anup Patnaik 1 , Laura Axford 2 , Lin Deng 3 , Evan Cohick 2 , Xianglin Ren 2 , Sally Loi 2 , Sam Kecman 2 , Micah Hollis-Symynkywicz 2 , Tyler J Harrison 1 , Julien P N Papillon 1 , Natalie Dales 1 , Lawrence G Hamann 1 , Lac Lee 2 , Jean B Regard 2 , Jovita Marcinkeviciene 2 , Martin L Marro 2 , Andrew W Patterson 1
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Myeloperoxidase (MPO) activity and subsequent generation of hypochlorous acid has been associated with the killing of host-invading microorganisms (e.g. bacteria, viruses, and fungi). However, during oxidative stress, high MPO activity can damage host tissue and is linked to several chronic inflammatory conditions. Herein, we describe the development of a novel biaryl, indole-pyrazole series of irreversible mechanism-based inhibitors of MPO. Derived from an indole-containing high-throughput screen hit, optimization efforts resulted in potent and selective pyrazole-indoles with good oral bioavailability and in vivo activity.
中文翻译：
发现了一种新型的吲哚药效团，可逆性抑制髓过氧化物酶（MPO）。
髓过氧化物酶（MPO）活性和次氯酸的后续产生与杀灭入侵宿主的微生物（例如细菌，病毒和真菌）有关。然而，在氧化应激期间，高的MPO活性会损害宿主组织，并与几种慢性炎症性疾病有关。在这里，我们描述了基于不可逆机制的MPO的新型联芳基，吲哚-吡唑系列的开发。源自含吲哚的高通量筛选结果，优化工作产生了具有良好口服生物利用度和体内活性的强效和选择性吡唑-吲哚。
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