Design, Synthesis and Biological Evaluation of Some 2-Azetidinone Derivatives as Potential Antihyperlipidemic Agents

• Published in: Archiv der Pharmazie (Weinheim) Vol. 346; no. 12; pp. 872 - 881
• Main Authors: Arya, Nikhilesh, Dwivedi, Jaya, Khedkar, Vijay M., Coutinho, Evans C., Jain, Kishor S.
• Format: Journal Article
• Language: English; German
• Published: WEINHEIM Blackwell Publishing Ltd 01.12.2013; Wiley; Wiley Subscription Services, Inc
• Subjects: 2-Azetidinone; Animals; Antihyperlipidemic; Azetidines - chemical synthesis; Azetidines - metabolism; Azetidines - pharmacology; Binding Sites; Biomarkers - blood; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Crystal structure; Crystallography, X-Ray; Disease Models, Animal; Drug Design; Ezetimibe; Female; Hyperlipidemias - blood; Hyperlipidemias - chemically induced; Hyperlipidemias - drug therapy; Hypolipidemic Agents - chemical synthesis; Hypolipidemic Agents - metabolism; Hypolipidemic Agents - pharmacology; Life Sciences & Biomedicine; Lipids - blood; Male; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Models, Molecular; Molecular docking; Molecular Docking Simulation; Molecular Structure; NPC1L1; Pharmacology & Pharmacy; Physical Sciences; Polyethylene Glycols; Protein Conformation; Rats; Rats, Wistar; Science & Technology; TRANS DIASTEREOSELECTIVE SYNTHESIS; DRUG; ACID; ANALOGS; Ezetimibe; Molecular docking; LIGANDS; NPC1L1; Antihyperlipidemic; 2-Azetidinone; STEREOSELECTIVE-SYNTHESIS; BLOCKING; BETA-LACTAMS
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201300262

In an effort to develop new molecules with improved antihyperlipidemic activity, eight new 2‐azetidinone analogs (4a–4h) of ezetimibe were designed through in silico docking experiments with the crystal structure of the Niemann‐Pick C1‐like 1 protein (NPC1L1). Synthesis and further antihyperlipdemic evaluation of this series in the Triton WR 1339 induced hyperlipidemic rat model showed some of the molecules to exhibit significant lipid‐lowering effects comparable to ezetimibe. Correlation between the observed biological activity and the in silico molecular docking scores of the compounds was observed. To develop new molecules with improved antihyperlipidemic activity, new 2‐azetidinone analogs (4a–4h) of ezetimibe were designed through in silico docking experiments with the crystal structure of the Niemann‐Pick C1‐like 1 protein (NPC1L1). Some of the molecules exhibited significant lipid lowering effects comparable to ezetimibe.