Zhao Haoyu, Sun Rongrong, Chen Lijuan, Chen Yong
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China.
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China.
Eur J Med Chem. 2025 Nov 5;297:117932. doi: 10.1016/j.ejmech.2025.117932. Epub 2025 Jul 5.
Acute liver injury (ALI) is a major pathological event in various liver diseases and remains a significant global medical challenge in terms of prevention and treatment. RIPK2, as a novel therapeutic target, has shown promise in the treatment of various inflammatory diseases, and it also holds potential for addressing acute liver injury. In this study, starting from a patent compound, computer-aided drug design and targeted structural optimization were employed to develop a new RIPK2 inhibitor with a thieno[3,2-d]pyrimidine core scaffold. Compound HY3 exhibited an IC of 11 nM against RIPK2, with high selectivity for RIPK2 over RIPK1. HY3 demonstrated favorable pharmacokinetic properties, with a bioavailability of 46.6 %, and displayed significant anti-inflammatory and hepatoprotective effects in an APAP-induced ALI model. These promising results suggest that HY3 warrants further preclinical and clinical development as a potential treatment for ALI.
急性肝损伤（ALI）是各种肝脏疾病中的主要病理事件，在预防和治疗方面仍然是一项重大的全球医学挑战。RIPK2作为一种新型治疗靶点，已在各种炎症性疾病的治疗中显示出前景，并且在解决急性肝损伤方面也具有潜力。在本研究中，从一种专利化合物出发，采用计算机辅助药物设计和靶向结构优化来开发一种具有噻吩并[3,2-d]嘧啶核心骨架的新型RIPK2抑制剂。化合物HY3对RIPK2的IC为11 nM，对RIPK2的选择性高于RIPK1。HY3表现出良好的药代动力学性质，生物利用度为46.6%，并且在对乙酰氨基酚诱导的ALI模型中显示出显著的抗炎和肝保护作用。这些有前景的结果表明，HY3作为ALI的潜在治疗药物值得进一步进行临床前和临床开发。
