Development of Thieno[3,2-d]pyrimidine derivatives as potent RIPK2 inhibitors with Prominent In vitro and In vivo anti-inflammatory efficacy

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-07-05 DOI:10.1016/j.ejmech.2025.117932

Haoyu Zhao , Rongrong Sun , Lijuan Chen , Yong Chen

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Abstract

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 IC₅₀ 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.

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Thieno[3,2-d]嘧啶衍生物作为有效的RIPK2抑制剂，具有显著的体外和体内抗炎作用

急性肝损伤（ALI）是各种肝脏疾病的主要病理事件，在预防和治疗方面仍然是一个重大的全球医学挑战。RIPK2作为一种新的治疗靶点，在多种炎症性疾病的治疗中显示出前景，并且在治疗急性肝损伤方面也具有潜力。本研究从一个专利化合物开始，采用计算机辅助药物设计和靶向结构优化的方法，开发了一种新的具有噻吩[3,2-d]嘧啶核心支架的RIPK2抑制剂。化合物HY3对RIPK2的IC50为11 nM，对RIPK2的选择性比RIPK1高。在apap诱导的ALI模型中，HY3表现出良好的药代动力学特性，生物利用度为46.6%，并表现出明显的抗炎和肝保护作用。这些有希望的结果表明，HY3作为ALI的潜在治疗方法值得进一步的临床前和临床开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.