Jaquet Vincent, Scapozza Leonardo, Clark Robert A, Krause Karl-Heinz, Lambeth J David
Department of Pathology and Immunology, Centre Médical Universitaire, School of Pharmaceutical Sciences, University of Geneva, Switzerland.
Antioxid Redox Signal. 2009 Oct;11(10):2535-52. doi: 10.1089/ars.2009.2585.
NOX NADPH oxidases are electron-transporting membrane enzymes whose primary function is the generation of reactive oxygen species (ROS). ROS produced by NOX enzymes show a variety of biologic functions, such as microbial killing, blood pressure regulation, and otoconia formation. Strong evidence suggests that NOX enzymes are major contributors to oxidative damage in pathologic conditions. Blocking the undesirable actions of NOX enzymes, therefore, is a therapeutic strategy for treating oxidative stress-related pathologies, such as ischemia/reperfusion tissue injury, and neurodegenerative and metabolic diseases. Most currently available NOX inhibitors have low selectivity, potency, and bioavailability, precluding a pharmacologic demonstration of NOX as therapeutic targets in vivo. This review has two main purposes. First, we describe a systematic approach that we believe should be followed in the search for truly selective NOX inhibitors. Second, we present a critical review of small-molecule NOX inhibitors described over the last two decades, including recently published patents from the pharmaceutical industry. Structures, activities, and in vitro/in vivo specificity of these NOX inhibitors are discussed. We conclude that NOX inhibition is a pertinent and promising novel pharmacologic concept, but that major efforts will be necessary to develop specific NOX inhibitors suited for clinical application.
NOX 烟酰胺腺嘌呤二核苷酸磷酸氧化酶是电子传递膜酶，其主要功能是产生活性氧（ROS）。NOX 酶产生的 ROS 具有多种生物学功能，如杀灭微生物、调节血压和耳石形成。有力证据表明，NOX 酶是病理状态下氧化损伤的主要促成因素。因此，阻断 NOX 酶的不良作用是治疗氧化应激相关疾病（如缺血/再灌注组织损伤、神经退行性疾病和代谢性疾病）的一种治疗策略。目前大多数可用的 NOX 抑制剂具有低选择性、低效能和低生物利用度，这使得无法在体内通过药理学方法证明 NOX 是治疗靶点。本综述有两个主要目的。第一，我们描述一种我们认为在寻找真正选择性 NOX 抑制剂时应遵循的系统方法。第二，我们对过去二十年中描述的小分子 NOX 抑制剂进行批判性综述，包括制药行业最近公布的专利。讨论了这些 NOX 抑制剂的结构、活性以及体外/体内特异性。我们得出结论，抑制 NOX 是一个相关且有前景的新型药理学概念，但开发适用于临床应用的特异性 NOX 抑制剂仍需付出巨大努力。
