Current Topics in Medicinal Chemistry

ISSN:1568-0266

Current Topics in Medicinal Chemistry
Volume 9, Number 5, 2009

Contents

New Medicinal Chemistry Approaches for the Treatment of Cardiovascular Disease
Guest Editor: Dennis Lee


Editorial Pp. 418
[Purchase Article]


Cholesteryl Ester Transfer Protein (CETP) Inhibitors Pp. 419-427
Julianne A. Hunt and Zhijian Lu
[Abstract] [Purchase Article]


HM74a Agonists: Will they be the New Generation of Nicotinic Acid? Pp. 428-435
Paul Martres
[Abstract] [Purchase Article]


Kv1.5 Blockers for the Treatment of Atrial Fibrillation: Approaches to Optimization of Potency and Selectivity and Translation to In Vivo Pharmacology Pp. 436-451
Mark T. Bilodeau and B. Wesley Trotter
[Abstract] [Purchase Article]


Soluble Epoxide Hydrolase, a Target with Multiple Opportunities for Cardiovascular Drug Discovery Pp. 452-463
Joseph P. Marino, Jr.
[Abstract] [Purchase Article]


Molecule of Month Pp. 464



Abstracts

[Back to top] [Purchase Article]
Editorial:

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.

The final two reviews in this issue focus on earlier stage, but promising areas of discovery. Atrial fibrillation increases the risk of stroke and congestive heart failure, and is a major contributor to morbidity and mortality. Current treatments are associated with significant side-effects such as ventricular arrhythmia (sodium channel blocker) and adverse effects on multiple tissues and organs (amiodarone). Bilodeau and Trotter provide a comprehensive review around the development of selective Kv1.5 blockers, and summarize the data which suggest that Kv1.5 is a key molecular target for maintaining or restoring sinus rhythm.

In the 4^th and final article, Marino reports on the development of inhibitors of soluble epoxide hydrolase (sEH), a target with several potential therapeutic opportunities in CV disease. sEH is an enzyme which metabolizes epoxyeicosatrienoic acid EET, which is believed to produce a variety of beneficial CV effects. Inhibition of EET metabolism by sEH could lead to therapeutic benefit in CV diseases of hypertension, inflammation and organ protection.

Despite the large number of CV medications already on the market, there remains a great need for new and improved therapies. However, drug development will be performed against a backdrop of existing medications and a more challenging regulatory environment in which outcome studies for indications such as diabetes and dyslipidemia will likely be the norm. Patient populations are large and getting larger, and significant opportunity to impact patient lives awaits those who are willing to invest in CV R&D.


Dennis Lee
Head, Chemistry and Preclincial Development, Ophthiris
GlaxoSmithKline Pharmaceuticals, RN0520
2301 Renaissance Blvd.
P.O. Box 61540
King of Prussia, PA
19406-2772
610 787-3871 (office)
610 592-7310 (mobile)


[Back to top] [Purchase Article]
Cholesteryl Ester Transfer Protein (CETP) Inhibitors
Julianne A. Hunt and Zhijian Lu

Epidemiological studies have demonstrated an inverse correlation between plasma concentrations of high-density 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.


[Back to top] [Purchase Article]
HM74a Agonists: Will they be the New Generation of Nicotinic Acid?
Paul Martres

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 HDL-Cholesterol. 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.


[Back to top] [Purchase Article]
Kv1.5 Blockers for the Treatment of Atrial Fibrillation: Approaches to Optimization of Potency and Selectivity and Translation to In Vivo Pharmacology
Mark T. Bilodeau and B. Wesley Trotter

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 I_Kur 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 non-selective 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.


[Back to top] [Purchase Article]
Soluble Epoxide Hydrolase, a Target with Multiple Opportunities for Cardiovascular Drug Discovery
Joseph P. Marino, Jr.

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.