Discovery of 2-azetidinone and 1H-pyrrole-2,5-dione derivatives containing sulfonamide group at the side chain as potential cholesterol absorption inhibitors

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• 作者：Xinrui Yuan ; Peng Lu ; Xiaojian Xue ; Hui Qin ; Chen Fan ; Yubin Wang ; ^{wyb5393@163.com" class="auth_mail" title="E-mail the corresponding author} ; Qi Zhang
• 关键词：2-Azetidinone ; 1H-Pyrrole-2 ; 5-dione ; Sulfonamide group ; Cholesterol absorption inhibitor ; Caco-2 cell line
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 February 2016
• 年：2016
• 卷：26
• 期：3
• 页码：849-853
• 全文大小：1403 K

文摘

Cholesterol absorption inhibitor (CAI) targeting Niemann-Pick C1-like1 protein was developed for the treatment of hyperlipidaemia and only ezetimibe was approved so far. For developing novel CAIs, we synthesized sixteen 2-azetidinone derivatives and thirteen 1H-pyrrole-2,5-dione derivatives containing sulfonamide group at the side chain, and their inhibitory activity of cholesterol absorption was evaluated in Caco-2 cell line in vitro. Furthermore, top six compounds were measured by cytotoxicity and partition coefficient, and 2-azetidinone analogue 9e was selected for in vivo study. Finally, 9e considerably reduced total cholesterol, LDL-C, FFA and triglyceride in the serum and increased the rate of HDL-C to total cholesterol, suggesting it could regulate the lipid metabolism and act as a potent CAI.