J W Clader, Schering-Plough Research Institute, Kenilworth, NJ, USA © 2007 Elsevier Ltd. All Rights Reserved.

8.07.1 Introduction

8.07.2 Discovery of the Prototype Azetidinone Cholesterol Absorption


66 68

8.07.3 Defining the Nature of the Target Structure-Activity Relationship on the Azetidinone Nucleus Rigid Analogs

8.07.4 The Discovery of Ezetimibe

8.07.5 Synthesis

8.07.6 Ezetimibe and Statins

8.07.7 Clinical Results

8.07.8 Mechanism of Action Studies

8.07.9 Conclusion References

77 80 80 80

8.07.1 Introduction

Atherosclerotic coronary artery disease remains a major cause of death and morbidity worldwide and a significant drain on healthcare resources, especially in developed countries. Cardiovascular disease claimed over 900000 lives in the USA in 2002. The World Health Organization (WHO) estimates that worldwide 17 million people die every year from cardiovascular disease, especially heart attack and stroke. The direct and indirect costs of cardiovascular disease are estimated to reach $393 billion in 2005.1

Of the many risk factors for cardiovascular disease, dyslipidemia is among the best understood and one that has clearly lent itself to both lifestyle and pharmacological intervention. Several large clinical studies conducted over the last few decades have indicated that overall mortality rates from cardiovascular disease can be significantly reduced with aggressive pharmacological intervention and risk factor management. Dietary counseling, exercise, and the use of drug therapy to reduce low-density lipoprotein (LDL) levels can significantly reduce the risk of developing coronary artery disease. While statins have dominated the market for pharmacotherapy, recent changes in the target LDL levels recommended by the National Cholesterol Education Program as well as a desire to limit the required dose of statins have highlighted the need for even more effective therapies.2-4

Ezetimibe is the first of a new class of drugs that treat hypercholesterolemia by inhibition of absorption of cholesterol from the intestines. While some intestinal cholesterol comes from the diet, the majority of the cholesterol that is absorbed from the intestines comes from the liver and has been excreted into the intestines in bile. Ezetimibe alone reduces LDL-C 15-18%, and adding ezetimibe to a starting dose of a statin produces a reduction in cholesterol levels equivalent to that seen with an eightfold higher statin dose.5-8 Ezetimibe has been the subject of a number of reports in the biological and medical literature.9-12

This case history traces the development of ezetimibe from the discovery of the first azetidinone cholesterol absorption inhibitors (CAIs) through the most recent information on the mechanism of action of this class of drugs. Beyond its significance as a new treatment for hypercholesterolemia, ezetimibe is of considerable interest because of the unusual path that led to its discovery. Although it began as a traditional medicinal chemistry effort, early in the program it became clear that ezetimibe and related azetidinone CAIs were not inhibiting cholesterol absorption via any known mechanism. Because of the absence of clear understanding of the molecular target, no in vitro assay existed to assess activity. As a result, every compound in this class had to be evaluated exclusively using in vivo models, most commonly in the cholesterol-fed hamster. Despite this limitation, these compounds displayed structure-activity relationships (SARs) that were well behaved and consistent with interaction with a structurally well-defined molecular target, although the nature of this target was unknown. Thus, the path that led to ezetimibe was arguably less technologically driven and more biology-based than typical drug discovery programs. The process relied heavily on hypothesis and experimentation to understand both the nature of the molecular target and how the activity of these compounds could be optimized. The history that is presented attempts to capture not only the facts and chronology of the discovery but also the thoughts, hypotheses, and milestones that led to an evolving understanding of the nature of the unknown biological target and how the activity of compounds could be optimized when a more targeted approach was not possible.13

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