2. Academic Validation
  3. 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

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

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: drwanghan2022@163.com.
  • 5 Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: yhmu@syphu.edu.cn.
  • 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: Wangshaojie@syphu.edu.cn.
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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