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合成及半合成黄嘌呤氧化酶抑制剂的全面综述:基于计算机模拟计算的ADME特性鉴定潜在先导化合物

A comprehensive review of synthetic and semisynthetic xanthine oxidase inhibitors: identification of potential leads based on in-silico computed ADME characteristics.

作者信息

Rana Rupali, Sharma Anchal, Kumar Nitish, Khanna Aanchal, Dhir Muskan, Gulati Harmandeep Kaur, Singh Jatinder Vir, Bedi Preet Mohinder Singh

机构信息

Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.

Drug and Pollution Testing Laboratory, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.

出版信息

Mol Divers. 2024 Aug 20. doi: 10.1007/s11030-024-10962-1.

Abstract

Xanthine oxidase (XO) inhibitors, both synthetic and semisynthetic, have been developed extensively over the past few decades. The increased level of XO is not only the major cause of gout but is also responsible for various conditions associated with hyperuricemia, such as cardiovascular disorders, chronic kidney disorders, diabetes, Alzheimer's disease and chronic wounds. Marketed available XO inhibitors (allopurinol, febuxostat, and topiroxostat) are used to treat hyperuricemia but they are associated with fatal side effects, which pose serious problems for the healthcare system, rising the need for new, more potent, safer compounds. This review summarizes recent findings on XO and describes their design, synthesis, biological significance in the development of anti-hyperuricemic drugs with ADME profile, structure activity relationship (SAR) and molecular docking studies. The results might help medicinal chemists to develop more efficacious XO inhibitors.

摘要

在过去几十年中,人们广泛开发了合成和半合成的黄嘌呤氧化酶(XO)抑制剂。XO水平升高不仅是痛风的主要原因,还与多种高尿酸血症相关病症有关,如心血管疾病、慢性肾脏疾病、糖尿病、阿尔茨海默病和慢性伤口。市售的XO抑制剂(别嘌醇、非布司他和托匹司他)用于治疗高尿酸血症,但它们伴有致命的副作用,这给医疗系统带来了严重问题,因此需要新的、更有效、更安全的化合物。本综述总结了关于XO的最新研究结果,并描述了它们的设计、合成、在具有药物代谢动力学性质的抗高尿酸血症药物开发中的生物学意义、构效关系(SAR)和分子对接研究。这些结果可能有助于药物化学家开发更有效的XO抑制剂。

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