Natural Substance Derivative DHNB is A Novel Xanthine Oxidase Inhibitor

描述（由申请人提供）：痛风是由高尿酸血症引起的，高尿酸血症是血液中尿酸水平异常高。一般人群中痛风患病率约为3.9%。此外，痛风和高尿酸血症的合并症也在增加，包括代谢综合征、高血压、高脂血症、慢性肾病、糖尿病和冠状动脉疾病。黄嘌呤氧化酶（XO）是参与嘌呤代谢的关键酶，是高尿酸血症和痛风治疗的主要靶点。目前针对XO的药物包括别嘌呤醇和非布司他，它们有许多副作用。临床上迫切需要用于此目的的新的、安全的和有效的药物。最近，我们首次发现，3，4-二羟基-5-硝基苯甲醛（DHNB），天然化合物原儿茶醛（3，4-二羟基苯甲醛）的衍生物，是一种有效的XO抑制剂在体外和体内。此外，我们已经表明，DHNB具有很强的清除过氧亚硝酸根和HOCl的作用，而别嘌呤醇缺乏这种效果。这项建议旨在 研究DHNB对小鼠高尿酸血症的疗效、药代动力学和毒性。具体而言，我们将确定DHNB对XO抑制的治疗效果，并研究DHNB在小鼠中的药代动力学;确定DHNB在小鼠中的潜在毒性;并确定DHNB是否与XO的FAD辅因子和/或钼辅因子相互作用。该项目的主要创新是发现和开发一种新的，有效的，安全的XO抑制剂，可用于临床治疗和预防痛风和高尿酸血症相关疾病。

DESCRIPTION (provided by applicant): Gout is caused by hyperuricemia, which is an abnormally high level of uric acid in the blood. Gout prevalence is about 3.9% for general population. In addition, comorbidities of gout and hyperuricemia are increasing, including metabolic syndrome, hypertension hyperlipidemia, chronic kidney disease, diabetes, and coronary artery disease. The key enzyme involved in purine catabolism is xanthine oxidase (XO), which is the major target for therapeutic treatment of hyperuricemia and gout. Current drugs targeting XO include Allopurinol and Febuxostat, which have many side effects. There is a pressing clinical need for new, safe and effective drugs for this purpose. Recently, we have discovered, for the first time, that 3,4-dihydroxy-5- nitrobenzaldehyde (DHNB), a derivative of the natural compound protocatechuic aldehyde (3,4- dihydroxybenzaldehyde), is a potent XO inhibitor in vitro and in vivo. In addition, we have shown that DHNB has a strong scavenging effect on peroxynitrite and HOCl, while Allopurinol lacks this effect. This proposal is designed to study the efficacy, pharmacokinetics and toxicity of DHNB for hyperuricemia in mice. Specifically, we will determine the therapeutic efficacy of DHNB for XO inhibition and study the pharmacokinetics of DHNB in mice; determine the potential toxicity of DHNB in mice; and determine whether DHNB interacts with the FAD cofactor and/or molybdenum cofactor of XO. The major innovation of the project is the discovery and development of a new, potent, and safe XO inhibitor which can be used clinically to treat and prevent gout and hyperuricemia-associated diseases.