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Editorial [Hot Topic: New Medicinal Chemistry Approaches for the Treatment of Cardiovascular Disease (Guest Editor: Dennis Lee)]

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Cardiovascular (CV) disease encompasses coronary heart disease (atherosclerosis), stroke, high blood pressure, heart failure, and several other conditions including arrhythmias, atrial fibrillation, cardiomyopathy and peripheral arterial disease. CV drug discovery over the past few decades has led to some of the most successful drugs on the market. Nevertheless, despite declining death rates in recent years, CV disease remains the leading cause of mortality in the United States, representing 35% of all deaths. Estimates from the year 2006 are that 80 million people in the US have one or more forms of CV disease. Factoring in the aging population and the increased prevalence of risk factors such as obesity, CV disease will continue to present as a significant healthcare challenge in the future, and will require new and improved medications for treatment.

This issue begins with reviews on the discovery and development of two different classes of lipid-modulating agents. Each has recently yielded clinical trial results that are both disappointing and surprising. Recent discovery efforts and clinical data in both areas are reviewed, with a focus on whether there is an issue with the target or molecules in development.

Epidemiological studies have shown that there is an inverse correlation between high-density lipoprotein cholesterol (HDL-C) levels in plasma and the incidence of coronary heart disease. Inhibition of cholesteryl ester transfer protein (CETP), which prevents the transfer of cholesterol from HDL to apoB-containing lipoproteins, originally held great promise for the improvement of CV outcomes of patients. In the first article of this issue, Hunt and Lu describe the development of CETP inhibitors. The first CETP inhibitor in large clinical studies, Torcetrapib, yielded desired effects on HDL-C and other lipids, but an increase in CV events was observed. Whether this is a CETP or off-target driven outcome remains to be determined, but the authors present clinical data on other CETP inhibitors which begin to address this question.

Nicotinic acid has been demonstrated to reduce the incidence of myocardial infarction and mortality. Its effects are believed to be through the lowering of triglycerides and LDL-cholesterol and concomitant increase of HDL-cholesterol. However, one third of patients discontinue treatment due to flushing, a cutaneous vasodilation resulting in increased skin temperature. Since the reporting of HM74a as the high affinity receptor for nicotinic acid in 2003, several groups have embarked on the discovery of agonists without the flushing side-effect. Martres summarizes the efforts thus far, including the unexpected lipid effects observed in recent clinical studies.
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Document Type: Research Article

Affiliations: Head, Chemistry and Preclincial Development, Ophthiris GlaxoSmithKline Pharmaceuticals, RN0520 2301 Renaissance Blvd. P.O. Box 61540 King of Prussia, PA 19406-2772.

Publication date: April 1, 2009

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