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

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

  • Eur J Med Chem. 2025 Nov 5:297:117932. doi: 10.1016/j.ejmech.2025.117932.
Haoyu Zhao 1,  Rongrong Sun 1,  Lijuan Chen 2,  Yong Chen 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China.
  • 2 State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China. Electronic address: chenlijuan125@163.com.
  • 3 Key Laboratory of Basic Pharmacology of Ministry of Education and School of Pharmacy, Zunyi Medical University, No.6 West Xuefu Road, Xinpu District, Zunyi, 563000, China. Electronic address: 18702896006@163.com.
PMID: 40639288 DOI: 10.1016/j.ejmech.2025.117932
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.

Keywords

Acute liver injury; Anti-inflammation; Pharmacokinetics; RIPK2.

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