Citation: Jia-Xi Huang, Chuang Xia, Le-Shen Li, Huichang Bi, Zhong-Zhen Zhou. Discovery of novel pyrrolopyrimidine-based PDE7 inhibitors against alcoholic liver injury[J]. Chinese Chemical Letters, ;2026, 37(11): 112245. doi: 10.1016/j.cclet.2025.112245 shu

Discovery of novel pyrrolopyrimidine-based PDE7 inhibitors against alcoholic liver injury

Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China

bihchang@smu.edu.cn

zhouzz@smu.edu.cn

Received Date: 14 September 2025
Revised Date: 8 December 2025
Accepted Date: 9 December 2025
Available Online: 10 December 2025

Figures(6)

Alcohol-associated liver disease (ALD) is responsible for a growing number of deaths and economic losses every year. However, there is no approved specific pharmacotherapy for alcoholic liver injury. Starting from the non-selective phosphodiesterase (PDE) inhibitor caffeine skeleton, we successfully identified a novel pyrrolo[2,3-d]pyrimidin-4-one derivative, ZHB12 (50% inhibitory concentration (IC₅₀) against PDE7A = 0.2 µmol/L), as a PDE7 inhibitor through the artificial intelligence (AI) driven "molecular factory" module. ZHB12 exhibits favorable physicochemical properties, good selectivity, and satisfactory bioavailability (F = 24.8%), as well as a non-toxic dose of 500 mg/kg. Additionally, ZHB12 demonstrated a significant therapeutic effect against alcoholic liver injury by increasing cyclic adenosine monophosphate (cAMP) levels and decreasing levels of inflammatory cytokines and transaminases. Notably, ZHB12 also reduced the abnormal levels of aminotransferases, inflammatory factors, and fibrosis-related genes in the alcoholic liver fibrosis (ALF) model mice, thereby improving ALF symptoms. These findings suggest that ZHB12 may be a promising candidate for the treatment of ALD.
- Alcohol-associated liver disease,
- Molecular factory,
- Pyrrolopyrimidine,
- PDE7 inhibitor,
- NIAAA model,
- Alcoholic liver fibrosis
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