Current Topics in Medicinal Chemistry - Volume 9, Issue 5, 2009

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.

Epidemiological studies have demonstrated an inverse correlation between plasma concentrations of highdensity lipoprotein cholesterol (HDL-C) and incidence of coronary heart disease (CHD); thus new therapies for raising HDL-C levels have been the focus of significant efforts by the cardiovascular medicine community. Inhibition of cholesteryl ester transfer protein (CETP) is one approach to increasing HDL-C concentrations. CETP is a plasma glycoprotein that mediates the transfer of cholesteryl esters from HDL to the apoB-containing lipoproteins, with a balanced transfer of triglycerides. Inhibition of CETP results in an accumulation of cholesteryl esters in HDL, thus resulting in increased HDL-C. Pharmacological inhibition of CETP in humans has been shown to result in increased levels of HDL-C, although any beneficial effect of this inhibition on CHD has yet to be established. This review article will discuss the complex role of CETP in lipid metabolism, recent developments for small-molecule inhibitors of CETP, and future prospects for CETP inhibitors in the treatment of CHD.

The discovery of HM74a as a high affinity receptor for nicotinic acid has opened up new areas for investigation. Since its discovery, several new chemical entities have been reported as HM74a agonists. One of them, MK-0354, has been tested in phase II studies, but despite significant decreases in Free Fatty Acid levels with absence of flushing events in clinical studies, it failed to demonstrate effects on LDL-Cholesterol, Triglycerides and HDLCholesterol. These surprising results lead to questions about the reality of HM74a as the unique receptor responsible for the lipid modulating effects of nicotinic acid. This review summarizes these recent developments, and the novel HM74a antagonist structures recently published.

The treatment and prevention of atrial fibrillation (AF) remains a significant unmet medical need. Existing therapies that maintain or restore sinus rhythm (rhythm control) have deleterious effects on the ventricle. A major goal for finding new AF therapies is the identification of repolarization mechanisms that are present in the atrium and not in the ventricle. The potassium current IKur has been shown to be selectively involved in atrial repolarization in human tissue. Hence this current and specifically Kv1.5, the protein that underlies it, have become prime targets for the invention of new AF agents. This article reviews the development of Kv1.5 blockers. The discovery and clinical progress of the nonselective Kv1.5 blockers vernakalant and AVE-0118 are highlighted. More selective Kv1.5 blockers in pre-clinical stages of discovery are then reviewed, with a focus on compounds that have been investigated for their in vivo effects on atrial repolarization or on efficacy in pre-clinical models of atrial fibrillation.

Soluble epoxide hydrolase (sEH) is a cross-functional target, with the potential for therapeutic utility in the areas of hypertension, inflammation, and organ-protection [1]. Promising target validation has emerged around soluble epoxide hydrolase in recent years which suggests that small molecule inhibitors may have utility in cardio protection, glucose regulation, hypertension, inflammation, and organ protection. Based on the diversity of chemical classes of sEH inhibitors reported in the literature, there exists a real opportunity to definitively determine the best therapeutic utility for an sEH inhibitor. Recent advances in target validation and tool compounds from medicinal chemistry efforts will be described.