title: Synthesis and in vitro evaluation of inhibitors of intestinal cholesterol absorption.
abstract: 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.
authors.affiliation: Laboratorium für Organische Chemie der ETH-Zürich, HCI H 335, Wolfgang Pauli Strasse 10, CH-8093, Zurich, Switzerland.
authors.forename: Lisbet
authors.initials: L
authors.lastname: Kvaernø
authors.forename: Moritz
authors.initials: M
authors.lastname: Werder
authors.forename: Helmut
authors.initials: H
authors.lastname: Hauser
authors.forename: Erick M
authors.initials: EM
authors.lastname: Carreira
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008871:Microvilli / Q000378:metabolism; D008958:Models, Molecular; D011817:Rabbits; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D006027:Glycosides; D047090:beta-Lactams; D002784:Cholesterol; D000069438:Ezetimibe