| Synthesis and in vitro evaluation of inhibitors of intestinal cholesterol absorption. | |
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MedLine Citation:
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PMID: 16162006 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have utilized our recently developed in vitro assay to address two key questions in the design of small-molecule cholesterol absorption inhibitors using ezetimibe, the only drug yet approved for the inhibition of cholesterol absorption in the small intestine, as a starting point: (1) the role of glycosylation and (2) the importance of the beta-lactam scaffold of ezetimibe for inhibitory activity. A wide range of nonhydrolyzable phenolic glycosides of ezetimibe were synthesized and demonstrated to be active inhibitors of cholesterol absorption using the brush border membrane vesicle assay. The analogous azetidines provided access to a variety of inhibitors in vitro, suggesting that the beta-lactam of ezetimibe merely serves as a ring scaffold to appropriately position the required substituents. Our findings highlight several promising strategies for the design of alternative small-molecule cholesterol absorption inhibitors that could ultimately be useful in preventing cardiovascular disease by lowering blood cholesterol levels. |
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Authors:
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Lisbet Kvaernø; Moritz Werder; Helmut Hauser; Erick M Carreira |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 48 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 2005 Sep |
Date Detail:
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Created Date: 2005-09-15 Completed Date: 2005-11-08 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 6035-53 Citation Subset: IM |
Affiliation:
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Laboratorium für Organische Chemie der ETH-Zürich, HCI H 335, Wolfgang Pauli Strasse 10, CH-8093, Zurich, Switzerland. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anticholesteremic Agents / chemical synthesis, chemistry, pharmacology* Azetidines / chemical synthesis, chemistry, pharmacology* Cholesterol / metabolism* Glycosides / chemical synthesis, chemistry, pharmacology Intestinal Absorption / drug effects* Intestine, Small / drug effects, metabolism, ultrastructure Microvilli / metabolism Models, Molecular Rabbits Structure-Activity Relationship beta-Lactams / chemical synthesis, chemistry, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Anticholesteremic Agents; 0/Azetidines; 0/Glycosides; 0/beta-Lactams; 163222-33-1/ezetimibe; 57-88-5/Cholesterol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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