Synthesis and anti-liver fibrosis activity of imidazole and thiazole compounds containing amino acids

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-03-13 DOI:10.1016/j.ejmech.2024.116311

Yu-Qing Meng , Jie Ren , Jing-Xin Sun , Fang-Yan Guo , Jun-Zhe Min , Ji-Xing Nan , Ji-Shan Quan , Li-Hua Lian , Cheng-Hua Jin

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Abstract

Four series of imidazoles (15a–g, 20c, and 20d) and thiazoles (18a–g, 22a, and 22b) possessing various amino acids were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. Among them, compounds 15g and 18c showed the highest inhibitory activity against ALK5, with IC₅₀ values of 0.017 and 0.025 μM, respectively. Compounds 15g and 18c efficiently inhibited extracellular matrix (ECM) deposition in TGF-β-induced hepatic stellate cells (HSCs), and eventually suppressed HSC activation. Moreover, compound 15g showed a good pharmacokinetic (PK) profile with a favorable half-life (t_1/2 = 9.14 h). The results indicated that these compounds exhibited activity targeting ALK5 and may have potential in the treatment of liver fibrosis; thus they are worthy of further study.

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含氨基酸的咪唑和噻唑化合物的合成及抗肝纤维化活性

研究人员合成了四个系列的咪唑类化合物（15a-g、20c和20d）和噻唑类化合物（18a-g、22a和22b），这些化合物具有不同的氨基酸，并在酶促实验中评估了它们对活化素受体样激酶5（ALK5）的抑制活性。其中，化合物 15g 和 18c 对 ALK5 的抑制活性最高，IC50 值分别为 0.017 和 0.025 μM。化合物 15g 和 18c 能有效抑制 TGF-β 诱导的肝星状细胞（HSCs）的细胞外基质（ECM）沉积，并最终抑制 HSC 的活化。此外，化合物 15g 表现出良好的药代动力学（PK）特征，具有良好的半衰期（t1/2 = 9.14 h）。研究结果表明，这些化合物具有靶向 ALK5 的活性，可能具有治疗肝纤维化的潜力，因此值得进一步研究。

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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.