Discovery of a Novel Thienopyrimidine Derivative as a Potent Dual URAT1/GLUT9 Inhibitor with Enhanced Urate-Lowering Efficacy, Superior Pharmacokinetics, and Favorable Safety Profile for Gout and Hyperuricemia

  • J Med Chem. 2026 May 28;69(10):11752-11775. doi: 10.1021/acs.jmedchem.5c02955.
Qian Yang  1 ,  Danhui Qi  1 ,  Wenjie Ye  2 ,  Xiaoyu Shi  1 ,  Mingyu Yang  1 ,  Ting Wu  2 ,  Zhenkun Wu  2 ,  Yuexin Xu  2 ,  Youzhao Wang  3 ,  Shujing Xu  1 ,  Zhenqian Wang  1 ,  Shenghua Gao  1 ,  Fan Yi  3 ,  Jianxin Pang  2 ,  Xinyong Liu  1 ,  Peng Zhan  1  4  5
Affiliations
  • 1. Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, Shandong Basic Science Special Academic Zone (Pharmacy), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan250012, Shandong, PR China.
  • 2. School of Pharmaceutical Sciences, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou510515, PR China.
  • 3. The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
  • 4. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Xue Yuan Rd. 38, Beijing100191, China.
  • 5. State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Institute of Pharmaceutical Research, Tianjin300301, China.
PMID: 42090242 DOI: 10.1021/acs.jmedchem.5c02955
Abstract

Gout and hyperuricemia, caused by high serum uric acid, require safer and more effective treatments due to the toxicity and limited efficacy of current drugs. Dual inhibition of URAT1 and GLUT9 may reduce renal toxicity compared to single-target approaches. Starting from lead compound F-5, we used scaffold hopping and structure-guided design to develop 46 novel polycyclic pyrimidine derivatives. Among these, compound 17 showed potent and balanced inhibition of URAT1 (IC50 = 4.01 μM) and GLUT9 (IC50 = 1.60 μM), greatly improving upon F-5. Additionally, 17 reduced serum uric acid levels by 82.4% in hyperuricemic mice, while it exhibited favorable pharmacokinetic profiles in rats (F = 33.71 vs 20.13% for F-5). Significantly, 17 was efficacious at a low dose (0.5 mg/kg) and showed no acute toxicity at 1000 mg/kg. These results support 17 as a promising dual URAT1/GLUT9 inhibitor with improved efficacy, pharmacokinetics, and safety for treating gout and hyperuricemia.

Products