title: Discovery of 2-azetidinone and 1H-pyrrole-2,5-dione derivatives containing sulfonamide group at the side chain as potential cholesterol absorption inhibitors.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Xinrui
authors.initials: X
authors.lastname: Yuan
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Xue
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Qin
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Fan
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China. Electronic address: wyb5393@163.com.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001384:Azetidines / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D018938:Caco-2 Cells; D002784:Cholesterol / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D005227:Fatty Acids / Q000097:blood; D057809:HEK293 Cells; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000077145:Sulfanilamide; D013424:Sulfanilamides / Q000737:chemistry*; D014280:Triglycerides / Q000097:blood
chemical_list: C116379:2-azetidinone; D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D005227:Fatty Acids; D011758:Pyrroles; D013424:Sulfanilamides; D014280:Triglycerides; D000077145:Sulfanilamide; D009569:Nitric Oxide; D002784:Cholesterol
keywords: 1H-Pyrrole-2,5-dione; 2-Azetidinone; Caco-2 cell line; Cholesterol absorption inhibitor; Sulfonamide group