Natural Substance Derivative DHNB is A Novel Xanthine Oxidase Inhibitor

天然物质衍生物DHNB是一种新型黄嘌呤氧化酶抑制剂

• 批准号: 8443691
• 负责人: Changyi Chen
• 金额: $ 16.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443691
• 关键词: Address; Adverse effects; Affect; Aged, 80 and over; Aldehydes; Allopurinol; Antioxidants; Applications Grants; Area Under Curve; Blood; Blood Chemical Analysis; Body Weight; Catabolism; Cell-Free System; Chemical Structure; Chronic Kidney Failure; Clinical; Comorbidity; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Elderly; Enzymes; Flavonoids; General Population; Gout; Health; Heart; Histology; Hyperlipidemia; Hypersensitivity; Hypertension; Hyperuricemia; In Vitro; Kidney; Life; Liver; Metabolic syndrome; Mus; Organ; Patients; Peroxonitrite; Pharmaceutical Preparations; Plasma; Potassium Oxonate; Prevalence; Prevention; Property; Purines; Reporting; Resistance development; Rosa; Series; Serum; Stevens-Johnson Syndrome; Syndrome; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Toxic Epidermal Necrolysis; Toxic effect; Treatment Efficacy; Uric Acid; Xanthine Oxidase; clinical application; clinically significant; cofactor; design; drug discovery; febuxostat; in vivo; innovation; male; molybdenum cofactor; novel; novel therapeutics; preclinical study; prevent; public health relevance; purine; research study; therapeutic target; xanthine oxidase inhibitor

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.

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异常高的尿酸。一般人群的痛风患病率约为3.9％。此外，痛风和高尿酸血症的合并症正在增加，包括代谢综合征，高血压高脂血症，慢性肾脏疾病，糖尿病和冠状动脉疾病。嘌呤分解代谢涉及的关键酶是黄嘌呤氧化酶（XO），它是高尿酸血症和痛风治疗的主要靶标。当前针对XO的药物包括异硫醇和FeBosostat，它们具有许多副作用。为此，迫切需要对新，安全有效的药物进行急需的临床需求。最近，我们第一次发现3,4-二羟基-5-硝基苯甲醛（DHNB）是天然化合物Protocatechuic醛（3,4-二羟基苯甲酰甲醛）的衍生物，是一种有效的XO XO XO XO Inbibor Inbibo Inbivo and Viv。此外，我们已经表明，DHNB对过氧亚硝酸盐和HOCL具有很强的清除作用，而别嘌醇缺乏这种作用。该建议旨在 研究DHNB对小鼠高尿酸血症的功效，药代动力学和毒性。具体而言，我们将确定DHNB对XO抑制的治疗功效，并研究小鼠DHNB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/或钼辅助因子相互作用。该项目的主要创新是发现和开发一种新的，有效和安全的XO抑制剂，该抑制剂可在临床上用于治疗和预防痛风和高尿素相关疾病。