Scaffold hopping-based structural modification of tranilast led to the identification of HNW005 as a promising NLRP3 inflammasome and URAT1 dual inhibitor for the treatment of gouty arthritis

  • Eur J Med Chem. 2025 Apr 17:292:117644. doi: 10.1016/j.ejmech.2025.117644.
Ming Sun  1 ,  Fengwei Lin  1 ,  Chenchen Yue  2 ,  Zijie Wei  2 ,  Chang Liu  1 ,  Dan Liu  3 ,  Xing Chen  1 ,  Qi Li  2 ,  Ziyuan Liu  1 ,  Jihong Han  2 ,  Zichen Cui  2 ,  Qing Mao  1 ,  Xinyu Li  1 ,  Peng Zhang  1 ,  Bing Zhang  1 ,  Xuefeng Fu  1 ,  Han Wang  4 ,  Yanhua Mou  5 ,  Shaojie Wang  6
Affiliations
  • 1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
  • 2. Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
  • 3. Shenyang Hinewy Pharmaceutical Technology Co., Ltd., Shenyang, Liaoning, 110016, PR China.
  • 4. Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, PR China. Electronic address: [email protected].
  • 5. Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
  • 6. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: [email protected].
PMID: 40286449 DOI: 10.1016/j.ejmech.2025.117644
Abstract

Hyperuricemia and monosodium urate induced NOD-like Receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation is the major pathogenesis for gouty arthritis, and urate transporter 1 (URAT1) is a proven target for hyperuricemia. In this study, scaffold hopping modification with tranilast led to the identification of HNW005, an NLRP3 inflammasome and URAT1 dual-target inhibitor, which exhibited notable inhibitory potency against NLRP3 inflammasome activation (KD = 204.6 nM, IC50 = 1.7 μM) and uric acid transmembrane transportation (IC50 = 6.4 μM). Importantly, HNW005 displayed significant in vivo efficacy with respect to anti-inflammatory, analgesic, and uric acid-lowering effects (decreasing rate = 64.8 % at 2 mg/kg). In addition, HNW005 also displayed an acceptable pharmacokinetic profile (F = 41.37 %, t1/2 = 3.07 h). Collectively, the results showed that developing dual-target inhibitors of NLRP3 inflammasomes and URAT1 is a feasible strategy for the treatment of gouty arthritis, and HNW005 is worthy of further investigation.

Keywords
Dual-target; Gouty arthritis; NLRP3 inflammasome; Tranilast analogs; Urate transporter 1.
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