Li Yun-Yun, Li Jing, Li Yan, Long Hong-Ping, Lin Wei, Wang Yi-Kun, Tang Rong, Liu Xue-Wu, Jiang Dejian, Liu Shao, Cao Dongsheng, Tan Gui-Shan, Xu Kang-Ping, Wang Wen-Xuan
Xiangya School of Pharmaceutical Sciences, Central South University Changsha Hunan 410008 PR China
Department of Pharmacy, National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South University Changsha Hunan 410008 PR China.
RSC Adv. 2024 Aug 2;14(33):24165-24174. doi: 10.1039/d4ra04626a. eCollection 2024 Jul 26.
Hyperuricemia, characterized by elevated uric acid levels and subsequent crystal deposition, contributing to conditions such as gout, cardiovascular events, and kidney injury, poses a significant health threat, particularly in developed countries. Current drug options for treatment are limited, with safety concerns, leading to suboptimal therapeutic outcomes in symptomatic hyperuricemia patients and a lack of pharmaceutical interventions for asymptomatic cases. Distinguishing from the previous drug design strategies, we directly target uric acid, the pathological molecule of hyperuricemia, resulting in a pyrimidine derivative capable of increasing the solubility and excretion of uric acid by forming a complex with it. Its prodrug showed an anti-hyperuricemia activity comparable to benzbromarone and a favorable safety profile . Our finding provides a strategy purely based on organic chemistry to address the largely unmet therapeutic needs on novel anti-hyperuricemia drugs.
高尿酸血症以尿酸水平升高及随后的晶体沉积为特征,可导致痛风、心血管事件和肾损伤等病症,对健康构成重大威胁,在发达国家尤为如此。目前的治疗药物选择有限,且存在安全问题,导致有症状的高尿酸血症患者治疗效果欠佳,无症状病例缺乏药物干预。与以往的药物设计策略不同,我们直接靶向高尿酸血症的病理分子尿酸,得到一种嘧啶衍生物,它能够与尿酸形成复合物,从而增加尿酸的溶解度和排泄。其前药显示出与苯溴马隆相当的抗高尿酸血症活性以及良好的安全性。我们的发现提供了一种完全基于有机化学的策略,以满足新型抗高尿酸血症药物在很大程度上未得到满足的治疗需求。