2. Academic Validation
  3. A Novel Pyrrole Acylsulfonamide, Compound 42, as a Dual URAT1/GLUT9 Inhibitor: Potent Urate-Lowering Efficacy, Reduced Off-Target Effects, and Promising Druggability for Hyperuricemia

A Novel Pyrrole Acylsulfonamide, Compound 42, as a Dual URAT1/GLUT9 Inhibitor: Potent Urate-Lowering Efficacy, Reduced Off-Target Effects, and Promising Druggability for Hyperuricemia

  • J Med Chem. 2026 May 14;69(9):10764-10787. doi: 10.1021/acs.jmedchem.6c00005.
Zhenqian Wang 1,  Xiaoyu Shi 1,  Zitao Guo 2,  Zhenkun Wu 2,  Yuexin Xu 2,  Mingyu Yang 1,  Mei Wang 1,  Qian Yang 1,  Ting Wu 2,  Jianxin Pang 2,  Fan Yi 3,  Peng Zhan 1 4 5,  Xinyong Liu 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P.R. China.
  • 2 School of Pharmaceutical Sciences, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou 510515, P.R. China.
  • 3 Department of Pharmacology, School of Medicine, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P.R. China.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 38 Xue Yuan Rd, Beijing 100191, P.R. China.
  • 5 State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine (Tianjin Institute of Pharmaceutical Research), Tianjin 300301, P.R. China.
PMID: 41997577 DOI: 10.1021/acs.jmedchem.6c00005
Abstract

Hyperuricemia and gout remain challenging due to the limited efficacy and safety of current therapies. Herein, we report a novel pyrrole acylsulfonamide, compound 42, rationally designed via structural simplification of lead compounds E1 and ZS-24, targeting urate transporters. In acute hyperuricemia mice, compound 42 demonstrated potent urate-lowering efficacy with a decrease ratio of 88.76%, significantly superior to Lesinurad (39.02%). Mechanistically, it synergistically inhibited URAT1 (IC50 = 2.81 ± 0.40 μM) and GLUT9 (IC50 = 12.53 ± 1.33 μM), with reduced off-target activity on OAT1 (IC50 = 7.83 ± 0.70 μM vs ZS-24's 4.90 ± 0.99 μM) to mitigate potential toxicity. It displayed superior ligand efficiency (LE = 0.44 vs ZS-24's 0.41) and favorable pharmacokinetics (T1/2 = 5.55 h, F = 51.3%). In hyperuricemic nephropathy mice, compound 42 reduced serum uric acid and protected renal function without acute and subacute toxicity at high doses, supporting its promise as a candidate for hyperuricemia and gout.

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