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

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.