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首页> 外文期刊>Nitric oxide: Biology and chemistry >Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases
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Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases

机译：硝基脂肪酸：用于慢性炎症和纤维化疾病的新药候选者

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Nitrated oleic acid (NO2-OA) was first identified in 2003, and after the characterization of its formation and thiol reactivity, it was used as a prototypical molecule to investigate the physiological actions of endogenous nitrated fatty acids (NO2-FA). Based on in vitro observations showing significant activation of cytoprotective and antiinflammatory signaling responses by NO2-FA, experiments were designed to determine their pharmacological potential. Supported by strong intellectual protection and favorable pharmacokinetic and pharmacodynamic data, 10-NO2-OA (CXA-10) underwent pharmaceutical development as a drug to treat fibrotic and inflammatory diseases. NO2-FA are at the intersection of three unconventional drug candidate classes that include 1) fatty acids, 2) metabolic intermediates and 3) electrophilic molecules. These three groups use different scaffolds for drug development, are characterized by broad activities and are individually gaining traction as alternatives to mono-target drug therapies. In particular, NO2-FA share key characteristics with currently approved pharmacological agents regarding reactivity, distribution, and mechanism of action. This review first presents the characteristics, liabilities, and opportunities that these different drug candidate classes display, and then discusses these issues in the context of current progress in the preclinical and clinical development of NO2-FA as drugs. Lessons learned from the novel approaches presented herein were considered early on during development to structurally define and improve NO2-FA and their disease targets.
机译：首先于2003年首次鉴定硝化油酸（NO2-OA），并且在其形成和硫醇反应性的表征之后，用作原型分子，以研究内源性硝化脂肪酸的生理作用（NO2-FA）。基于在NO2-FA的含有显着激活细胞保护和抗炎信号响应的体外观察的基础上，设计实验以确定其药理潜力。通过强烈的智力保护和有利的药代动力学和药效学数据，10-NO 2-OA（CXA-10）接受药物开发作为治疗纤维化和炎症性疾病的药物。 NO2-FA处于三种非传统药物候选类别，包括1）脂肪酸，2）代谢中间体和3）亲电分子。这三组使用不同的支架进行药物发育，其特征在于广泛的活动，并单独获得牵引力作为单靶药疗法的替代品。特别是，NO2-FA共享关于关于反应性，分布和行动机制的目前批准的药理学药物的关键特征。本次审查首先介绍了这些不同毒品候选课程展示的特点，负债和机会，然后在NO2-FAIS患者的临床前和临床开发中讨论了这些问题。从本文提出的新方法中学到的经验教训在开发期间考虑到在结构上定义和改善NO2-FA及其疾病目标。

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