Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 2, Issue 3, 2007

Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect, in a concerted manner, a multitude of the cardiometabolic risk factors associated with diabetes, obesity, and the metabolic syndrome. Studies in ACC2 knockout mice and in experimental animals treated with isozymespecific antisense oligonucleotides or with isozyme-nonselective ACC inhibitors have demonstrated the potential for treating metabolic syndrome through this modality. Co-crystallization of the biotin carboxylase and carboxyltransferase domains of eukaryotic ACC in the presence of substrates and inhibitors has revealed characteristics of the catalytic center that can be exploited in drug discovery. A variety of structurally diverse, mechanistically distinct classes of ACC inhibitors have been disclosed in the scientific and patent literature. Isozyme-nonselective ACC inhibitors may provide the optimal therapeutic potential. However, demonstration of the full potential of isozyme-selective inhibitors, once identified, should reveal advantages and liabilities associated with single isozyme inhibition.

The most common symptom of lower extremity peripheral arterial disease (PAD) is intermittent claudication. The severity of PAD is closely related with the risk of myocardial infarction, ischaemic stroke, and death from vascular causes. Despite the higher prevalence of PAD, far less importance is given to its diagnosis and management. Patients with peripheral arterial disease should be offered secondary prevention strategies including aggressive risk factor modification and anti-platelet drug therapy. Cilostazol, a reversible, selective inhibitor of PDE III with antiplatelet, antithrombotic and vasodilatory effects, was approved by the FDA in 1999 for the treatment of Intermittent Claudication. It is believed that the collective pharmacology effect of cilostazol actually improves blood flow to the lower extremities. The efficacy of cilistazol has been demonstrated in eight Phase three clinical trials. Cilostazol is the first drug to consistently demonstrate clinical efficacy in many double-blind randomised control trials. It is indicated for the improvement of the maximal and pain-free walking distances in patients with IC, who do not have rest pain and who do not have evidence of peripheral tissue necrosis. In this review we highlight the role of Cilostazol in the management of peripheral arterial disease. The combined effect of aspirin with Cilostazol was recently patented.

Close to 60 matrix metalloproteinase (MMP) inhibitors have been pursued as clinical candidates since the first drug discovery program targeting this enzyme family began in the late seventies. Targeted indications included cancer, arthritis, cardiovascular diseases, and many others. However, the clinical development of most of the MMP inhibitors have been discontinued due to safety reasons and so far only Periostat (doxycycline hyclate, a nonspecific MMP inhibitor) has been approved for periodontal disease. Because of the high therapeutic potential, the development of MMP inhibitors continues as shown by several recent patents and scientific publications. Development of selective MMP inhibitors lacking serious side-effects such as musculoskeletal syndrome is of high importance. Innovative approaches for the design of selective MMP inhibitors include the integration of classical medicinal chemistry structure-based properties and design features into the emerging chemogenomics concept of target-family based drug discovery. This approach, which includes privileged structures, molecular frameworks, bioisosteric and bioanalogous/isofunctional modifications (the “matrixinome” approach), may lead to highly selective MMP inhibitors in the future.

The goal of drugs is to modulate the activity of particular gene products in order to change the physiological state of an organism from disease to health. Because of the complexity of development and metabolism, it is difficult to extrapolate from in vitro experimental results using purified reagents, to predict the actual change in behavior of an entire biological system in vivo. Metabolic control analysis provides a theoretical framework for understanding the basis of this apparent paradox. In practice, genetics provides a unique opportunity to observe the behavior of whole systems in the presence of different amounts of a particular gene product, resulting from varying genomic sequences of alleles governing the expression or activity of that gene product. This is most evident in the case of monogenic disorders, in which severe mutations in a gene lead to clear effects on gene product activity, and strong causal genotype/phenotype correlations can be inferred. Among the many therapeutic targets currently in development for treatment of dyslipidemia, a major risk factor for cardiovascular disease, there is particular interest in those targets whose coding genes are associated with molecularly characterized monogenic human conditions. Herein a selection of these genetic disorders, especially those involving HDL and LDL cholesterol, is discussed in the context of ongoing or potential therapeutic development programs. This article also includes recent patent review coverage.

Treatment of patients with heart failure secondary to myocardial infarction remains a therapeutic challenge. Extensive myocyte death in the heart and post-ischemic remodeling accentuate progressive expansion of the scar area and compromise left ventricular contractile function. The scarcity of resident stem cells in the heart and limited proliferative capacity of adult cardiomyocytes warrant novel strategies of outside intervention to supplement the inept intrinsic repair mechanism. Heart cell therapy using patient's own skeletal muscle derived myoblasts (SkMs) provides a relatively simple and inexpensive therapeutic option. Phase-I and II clinical trials supported by plethora of pre-clinical studies have shown the safety and effectiveness of SkMs engraftment in the treatment of infarcted heart. However, before widespread application of this approach in the clinical settings, there remain some fundamental issues including extensive donor cell death during acute phase after SkMs engraftment, failure of SkMs to adopt cardiac phenotype and transient ventricular arrhythmias subsequent to SkMs transplantation which require serious considerations. This review will provide profound analysis of merits and limitations of SkMs as the choice cells for heart cell therapy and will summarize the potential of genetic and pharmacological manipulation SkMs to enhance their therapeutic efficacy for myocardial repair. Present article also includes recent patent review coverage on this topic.

High density lipoprotein (HDL) has proven its role in reverse cholesterol transport and cellular cholesterol efflux thus acting as a protective factor against atherogenic cardiovascular diseases. The article focuses primarily on structure and function of genes influencing HDL metabolism. Various novel targets involve liver X receptor, retinoid X receptor, peroxisome proliferators activated receptor agonists and apoA-I mimetics. New molecules targeting these nuclear receptors are described. Phospholipid transfer protein and scavenger receptor B1 are also attractive targets in HDL metabolism. ATP-Binding Cassette transporter A1 and several lipases also play a crucial role in HDL metabolism and are very useful target for atherogenic dyslipidemia. Cholesteryl ester transfer protein inhibitors have shown great promise as possible drug candidates of future. Notably, JTT-705 (Japan Tobacco, Roche) is of great interest in spite of withdrawal of torcetrapib. Considering modest effect of currently available therapeutic options on HDL, these novel HDL elevating targets are doubtlessly the target for future atherosclerotic intervention.

Cardiovascular disease has become the global leading cause of death worldwide, representing the most frequent cause of morbidity and mortality in the developed world. Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Meta-analyses from several primary and secondary intervention studies have clearly shown that cholesterol-lowering medication, significantly reduces cardiovascular events, mortality, and morbidity, but considerable interindividual variation exists in response to statin therapy. Pharmacogenomics can provide important insights into statins therapy through elucidation of the genetic (or genomic) contribution to variable response for these drugs. The search for genetic polymorphisms may enable us to identify novel determinants of drug responsiveness by means of the study of three candidate genes groups: (1) genes encoding proteins involved in metabolism or drug transport, or both, that influence drug pharmacokinetics; (2) genes encoding proteins involved in mechanism of action and/or metabolic pathways on which drugs operate (that influence pharmacodynamics); (3) genes encoding proteins involved in the underlying disease condition or intermediate phenotype. This review briefly summarizes the recent pharmacogenomic and pharmacogenetic patents and the potential contributions of genetic variations in candidate genes related to lipid and lipoprotein metabolism and statins efficacy.

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