Jin Qihui, Wu Tom Y-H
Nexys Therapeutics Inc., 9276 Scranton Rd, Ste 500, San Diego, California 92121, United States.
ACS Med Chem Lett. 2025 May 8;16(6):1163-1169. doi: 10.1021/acsmedchemlett.5c00204. eCollection 2025 Jun 12.
Gout is a metabolic disorder characterized by excessive uric acid accumulation, often managed by uric acid transporter 1 (URAT1) inhibitors. However, existing URAT1 inhibitors such as lesinurad and benzbromarone present significant kidney and liver toxicity risks, respectively. To address these limitations, we designed and optimized a novel series of 6-azaindole URAT1 inhibitors, culminating in the lead candidate . demonstrated a favorable pharmacokinetic (PK) profile with a lower peak-to-trough ratio compared to lesinurad, suggesting slower renal clearance and a reduced risk of uric acid microcrystallization in the kidneys. Additionally, exhibited no glutathione (GSH) trapping, unlike benzbromarone, indicating reduced risk of reactive metabolites formation and a lower potential for idiosyncratic liver toxicity. These findings highlight as a promising next-generation URAT1 inhibitor with improved safety profile, warranting further investigations.
痛风是一种以尿酸过度积累为特征的代谢紊乱疾病，通常由尿酸转运蛋白1（URAT1）抑制剂进行治疗。然而，现有的URAT1抑制剂，如雷西纳德和苯溴马隆，分别存在显著的肾脏和肝脏毒性风险。为了解决这些局限性，我们设计并优化了一系列新型的6-氮杂吲哚URAT1抑制剂，最终得到了先导候选药物。与雷西纳德相比，该候选药物显示出良好的药代动力学（PK）特征，峰谷比更低，这表明其肾脏清除速度较慢，肾脏中尿酸微晶化的风险降低。此外，与苯溴马隆不同，该候选药物没有谷胱甘肽（GSH）捕获现象，这表明其形成反应性代谢物的风险降低，发生特异质性肝毒性的可能性较小。这些发现突出了该候选药物作为一种具有改善安全性的下一代URAT1抑制剂的潜力，值得进一步研究。
