Singh Atamjit, Singh Karanvir, Sharma Aman, Kaur Kirandeep, Chadha Renu, Singh Bedi Preet Mohinder
Department of Pharmaceutical Sciences, Guru Nanak Dev University Amritsar Punjab 143005 India
University Institute of Pharmaceutical Sciences, Panjab University Chandigarh 160014 India.
RSC Med Chem. 2023 Aug 7;14(11):2155-2191. doi: 10.1039/d3md00316g. eCollection 2023 Nov 15.
Xanthine oxidase, a molybdo-flavoenzyme, and an isoform of xanthine dehydrogenase both exist as xanthine oxidoreductase and are responsible for purine catabolism. Xanthine oxidase is more involved in pathological conditions when extensively modulated. Elevation of xanthine oxidase is not only the prime cause of gout but is also responsible for various hyperuricemia associated pathological conditions like diabetes, chronic wounds, cardiovascular disorders, Alzheimer's disease, Currently available xanthine oxidase inhibitors in clinical practice (allopurinol, febuxostat and topiroxostat) suffer from fatal side effects that pose a serious problem to the healthcare system, raising global emergency to develop novel, potent and safer xanthine oxidase inhibitors. This review will provide key and systematic information about: a. design strategies (inspired from both marketed drugs in clinical practice and natural products), structural insights and pharmacological output (xanthine oxidase inhibition and associated activities) of various pre-clinical candidates reported by various research groups across the globe in the past two decades; b. patented xanthine oxidase inhibitors published in the last three decades and c. clinical trials and their outcomes on approved drug candidates. Information generated in this review has suggested fragment-based drug design (FBDD) and molecular hybridization techniques to be most suitable for development of desired xanthine oxidase inhibitors as one provides high selectivity toward the enzyme and the other imparts multifunctional properties to the structure and both may possess capabilities to surpass the limitations of currently available clinical drugs. All in combination will exclusively update researchers working on xanthine oxidase inhibitors and allied areas and potentially help in designing rational, novel, potent and safer xanthine oxidase inhibitors that can effectively tackle xanthine oxidase related disease conditions and disorders.
黄嘌呤氧化酶是一种钼黄素酶，也是黄嘌呤脱氢酶的一种同工型，两者均以黄嘌呤氧化还原酶的形式存在，负责嘌呤分解代谢。当受到广泛调节时，黄嘌呤氧化酶在病理状况中发挥更大作用。黄嘌呤氧化酶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的病理状况有关，如糖尿病、慢性伤口、心血管疾病、阿尔茨海默病。目前临床实践中可用的黄嘌呤氧化酶抑制剂（别嘌醇、非布司他和托匹司他）存在致命副作用，给医疗系统带来严重问题，这促使全球迫切需要开发新型、高效且更安全的黄嘌呤氧化酶抑制剂。本综述将提供有关以下方面的关键且系统的信息：a. 过去二十年来全球各研究小组报道的各种临床前候选药物的设计策略（灵感来自临床实践中的上市药物和天然产物）、结构见解和药理作用（黄嘌呤氧化酶抑制及相关活性）；b. 过去三十年中公布的黄嘌呤氧化酶抑制剂专利；c. 临床试验及其对获批候选药物的结果。本综述所产生的信息表明，基于片段的药物设计（FBDD）和分子杂交技术最适合开发所需黄嘌呤氧化酶抑制剂，因为前者对该酶具有高选择性，后者赋予结构多功能特性，两者都可能具备超越现有临床药物局限性的能力。所有这些结合起来将专门为从事黄嘌呤氧化酶抑制剂及相关领域研究的人员提供最新信息，并可能有助于设计合理、新颖、高效且更安全的黄嘌呤氧化酶抑制剂，从而有效应对与黄嘌呤氧化酶相关的疾病状况和紊乱。
