Kvaernø Lisbet, Werder Moritz, Hauser Helmut, Carreira Erick M
Laboratorium für Organische Chemie der ETH-Zürich, HCI H 335, Wolfgang Pauli Strasse 10, CH-8093, Zurich, Switzerland.
J Med Chem. 2005 Sep 22;48(19):6035-53. doi: 10.1021/jm050422p.
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.
我们利用最近开发的体外试验，以依折麦布（唯一已获批用于抑制小肠胆固醇吸收的药物）为起点，解决小分子胆固醇吸收抑制剂设计中的两个关键问题：（1）糖基化的作用；（2）依折麦布的β-内酰胺骨架对抑制活性的重要性。合成了多种依折麦布的非水解性酚糖苷，并通过刷状缘膜囊泡试验证明它们是胆固醇吸收的活性抑制剂。类似的氮杂环丁烷在体外提供了多种抑制剂，这表明依折麦布的β-内酰胺仅作为一个环骨架，用于适当定位所需的取代基。我们的研究结果突出了几种有前景的策略，可用于设计替代性小分子胆固醇吸收抑制剂，最终可能有助于通过降低血液胆固醇水平来预防心血管疾病。
