Discovery of a Potent and Orally Bioavailable Xanthine Oxidase/Urate Transporter 1 Dual Inhibitor as a Potential Treatment for Hyperuricemia and Gout

作者：Xinye Yang, Yong Li, Shengqiang Pan, Facheng Ma, Hong Chen, Jinhui Deng, Jie Yue, Qijie Gong, Mi Zheng, Ying Zeng, Jing Li, Ying‐Jun Zhang, Xiaojun Wang, Xiaojin Zhang · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c01480 · 被引用次数：17 · 研究领域：Gout, Hyperuricemia, Uric Acid、Case Reports on Hematomas、Eosinophilic Disorders and Syndromes

The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat ( 2 ) and the URAT1 inhibitor probenecid ( 3 ), followed by structure–activity relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (XO IC 50 = 35 nM; URAT1 IC 50 = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound 27 emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.