Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China.
Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China.
Bioorg Chem. 2024 Sep;150:107536. doi: 10.1016/j.bioorg.2024.107536. Epub 2024 Jun 5.
Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.
羧酸酯酶 1（CES1）是丝氨酸水解酶超家族的成员，参与哺乳动物中外源物质和内源性物质的广泛代谢反应。CES1 的抑制不仅可以改变相关药物的代谢和处置，而且有助于治疗代谢紊乱，如肥胖和脂肪肝疾病。在本研究中，我们旨在开发 CES1 的潜在抑制剂，并从一系列合成吡唑酮（化合物 1-27）中揭示首选抑制剂结构。通过体外高通量筛选方法，我们发现化合物 25 和 27 对 CES1 介导的 N-烷基化 d-荧光素甲酯（NLMe）水解具有非竞争性抑制作用，而化合物 26 竞争性抑制 CES1 介导的 NLMe 水解。此外，化合物 25、26 和 27 可以在活 HepG2 细胞中抑制 CES1 介导的荧光探针水解。此外，化合物 25、26 和 27 可以有效抑制小鼠脂肪细胞中脂滴的积累。这些数据不仅为设计新型 CES1 抑制剂提供了研究基础。本研究不仅为开发具有更好性能的新型 CES1 抑制剂的先导化合物提供了基础，而且为探索治疗高血脂症和相关疾病的候选化合物提供了新的方向。
