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.
This is a R21 grant proposal (resubmission) to determine pharmacologic mechanisms, therapeutic efficacy and major pharmacokinetics of a natural substance derivative DHNB as a novel xanthine oxidase inhibitor for the treatment of gout and hyperuricemia. This project represents the drug discovery and pre- clinical study for the development of a novel therapeutic agent for gout and hyperuricemia.
|Chen, Changyi; LÃ¼, Jian-Ming; Yao, Qizhi (2016) Hyperuricemia-Related Diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview. Med Sci Monit 22:2501-12|
|Lu, Jian-Ming; Yao, Qizhi; Chen, Changyi (2013) 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout. Biochem Pharmacol 86:1328-37|