-Lactam Cholesterol Absorption Inhibitors

Author: Burnett D.A.

Source: Current Medicinal Chemistry, Volume 11, Number 14, July 2004 , pp. 1873-1887(15)

Publisher: Bentham Science Publishers

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Abstract:

-Lactams have recently been identified as potent, highly efficacious cholesterol absorption inhibitors (CAIs). The discovery, SAR, and asymmetric synthesis of this class of hypolipidemic agents are described. Metabolism studies of the first clinical candidate, Sch 48461, led to the identification of a more potent second generation clinical candidate, Sch 58235 (ezetimibe) incorporating key structural elements of the active metabolites. A summary of preclinical and early clinical studies of ezetimibe as monotherapy and in combination with statins is also presented. Efforts to identify a pharmacophore model has led to the development of conformationally constrained analogs and analogs with conformational biases based on intramolecular hydrogen bonding possibilities. Finally, mechanism of action studies have led to the development of many biochemical tools for the investigation and identification of novel proteins involved in cholesterol uptake.

Keywords: actam Cholesterol; ezetimibe; hypolipidemic agents; pharmacophore model; intramolecular hydrogen bonding

Document Type: Review article

DOI: http://dx.doi.org/10.2174/0929867043364865

Affiliations: 1: Discovery Chemistry - CNS / CV, Schering-Plough Research Institute, 2015 Galloping Hill Rd., MS 2800, Kenilworth, NJ, 07033; USA

Publication date: 2004-07-01

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Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.