Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability

  • J Med Chem. 2024 Mar 28;67(6):5032-5052. doi: 10.1021/acs.jmedchem.4c00136.
Xiaoyu Shi  1 ,  Tong Zhao  1 ,  Shuo Wang  1 ,  Shujing Xu  1 ,  Hui Liao  2 ,  Shenghua Gao  1 ,  Zhen Gao  1 ,  Jian Zhang  1 ,  Danhui Qi  1 ,  Zhijiao Zhang  1 ,  Fengxin Zheng  2 ,  Youzhao Wang  3 ,  Zhenqian Wang  1 ,  Mingyu Yang  1 ,  Qian Yang  1 ,  Fan Yi  3 ,  Jianxin Pang  2 ,  Xinyong Liu  1 ,  Peng Zhan  1
Affiliations
  • 1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan, 250012 Shandong, PR China.
  • 2. School of Pharmaceutical Sciences, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou 510515, 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.
PMID: 38482820 DOI: 10.1021/acs.jmedchem.4c00136
Abstract

Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with Xanthine Oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 μM) and glucose transporter 9 (GLUT9, IC50 = 18.21 μM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

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