Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 5, Issue 3, 2007

Thrombosis is the condition where an imbalance in the homeostatic mechanism results in unwanted intravascular thrombus formation. Imbalances in this highly regulated process of coagulation and anticoagulation can lead to a variety of pathophysiological conditions leading to stroke, pulmonary heart attack and other serious conditions. In the western world, thromboembolic diseases are the leading cause of morbidity and mortality. Remarkable progress has occurred over the last decade in the development of antithrombotic drugs, which can be classified into 3 major categories - Anticoagulants, Antiplatelets and thrombolytics. Increased understanding of the pathobiology of thrombotic and vascular disorders has helped researchers to target novel pathways involving the coagulation, thrombolytic, fibrinolytic and integrin systems. Traditionally aspirin and unfractionated heparin was used for myocardial infarction. Newer antiplatelet agents such as, clopidogrel, GP IIb/IIIa inhibitors, low molecular weight heparin, direct thrombin inhibitors and several improved thrombolytic agents have been introduced for clinical use. This review will discuss different important drugs, which have been launched in recent years and also some new targets pursued by different companies.

Awareness of the importance of carbohydrates in living systems and medicine is growing due to the increasing understanding of their biological and pharmacological relevance. Carbohydrates are ubiquitous and perform a wide array of biological roles. Carbohydrate-based or -modified therapeutics are used extensively in cardiovascular and hematological treatments ranging from inflammatory diseases and anti-thrombotic treatments to wound healing. Heparin is a wellknown and widely used example of a carbohydrate-based drug but will not be discussed as it has been extensively reviewed. We will detail carbohydrate-based and -modified therapeutics, both those that are currently marketed or in various stages of clinical trials and those that are potential therapeutics based on promising preclinical investigations. Carbohydrate- based therapeutics include polysaccharide and oligosaccharide anti-inflammatory, anti-coagulant and antithrombotic agents from natural and synthetic sources, some as an alternative to heparin and others which were designed based on known structure-functional relationships. Some of these compounds have multiple biological effects, showing anti-adhesive, anti-HIV and anti-arthrithic activities. Small molecules, derivatives or mimetics of complement inhibitors, are detailed for use in limiting ischemia/ reperfusion injuries. Monosaccharides, both natural and synthetic, have been investigated for their in vivo anti-inflammatory and cardioprotective properties. Modification by glycosylation of natural products, or glycosylation-mimicking modification, has a significant effect on the parent molecule including increased plasma half-life and refining or increasing desired functions. It is hoped that this review will highlight the vast therapeutic potential of these natural bioactive molecules.

The molecular pathogenesis of the myeloproliferative disorders (MPD) is poorly understood, except for chronic myeloid leukemia (CML). Recently, several groups have discovered a novel recurrent unique acquired clonal mutation in a tyrosine-kinase JAK2 in patients with Philadelphia-negative MPD and other myeloid disorders. It consists in a guanineto- thymine change encoding a valine to phenylalanine at codon 617 (JAK2 V617F). JAK2 and the other members of the Janus kinase family are tyrosine kinases that function as intermediates between membrane receptors and intracellular signalling molecules. The mutation occurs within the enzymatically inactive JH2 pseudo-kinase domain that regulates the active JH1 kinase domain. The JAK2 activation leads to constitutive JAK and STAT (activators of transcription) hyperactivation with induction of growth factor hypersensitivity and cell transformation. Some authors have found a higher risk of vascular thrombosis and higher platelet activation when the mutation is present. Therefore, the JAK2 mutation offers a molecular target for new drugs investigation in a similar way to bcr/abl rearrangement in CML. For all these reasons, several studies related to JAK2 have arisen in the last year. In this report, we will review the literature and discuss its possible clinical and prognostic significance.

Nitric oxide (NO) is a molecule that dynamically modulates the physiological functions of the cardiovascular system, which include relaxation of vascular smooth muscle, inhibition of platelet aggregation, and regulation of immune responses. Because a reduced NO level has been implicated in the onset and progression of various disease states, NO is expected to provide therapeutic benefits in the treatment of cardiovascular diseases, such as essential hypertension, stroke, coronary artery disease, atherosclerosis, platelet aggregation after percutaneous transluminal coronary angioplasty, and ischemia/reperfusion injury. To date, pharmacologically active compounds that can release NO within the body, such as organic nitrates and sodium nitroprusside, have been used as therapeutic agents, but their efficacy is significantly limited by their rapid NO release, poor distribution to the target site, toxicity, and induction of tolerance. Therefore, new NO donors with better pharmacological and pharmacokinetic properties would be highly desirable. In this review, recent challenges in the development of new NO donors and NO delivery systems are summarized. Then, future developments of novel NO donors are also discussed in order to optimize NO delivery in the treatment of cardiovascular diseases.

Metabolic syndrome is defined as the combination of abdominal obesity, insulin resistance, atherogenic dyslipidemia, and prothrombotic and proinflammatory states. Due to the epidemic proportion of overweight and obesity worldwide and the development of useful clinical tools to identify these patients more easily, metabolic syndrome is increasingly recognized in adults and represents a clear risk factor for the development of both type 2 diabetes and cardiovascular disease. Management of patients with metabolic syndrome is a clinical challenge and requires a multifactorial, multidisciplinary approach. Changes in lifestyle are obviously the first therapeutic step and include both dietary modifications and increased daily exercise. Several questions remain to be elucidated with respect to pharmacological treatment. The blood pressure levels required to initiate antihypertensive treatment, the blood pressure goal to be achieved and the possibility of including a renin-angiotensin system blocker as a part of the pharmacological treatment are still under discussion. The management of atherogenic dyslipidemia is focused on LDL-cholesterol levels, although most patients with metabolic syndrome have normal LDL-cholesterol. There is lack or poor evidence on the need for specific drugs to reduce triglycerides, to increase HDL-cholesterol, to improve insulin sensitivity or to decrease abdominal obesity. There is an urgent need for consensus in the treatment of subjects with metabolic syndrome in order to prevent very high future rates of type 2 diabetes and cardiovascular disease.

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. Statins are widely and successfully used for lowering plasma cholesterol levels causing up to 45% reduction of plasma cholesterol and considerable reduction in risk of cardiovascular diseases. The main atheroprotective action of statins is reduction of plasma low density lipoprotein levels due to improved clearance of this lipoprotein by the liver. In addition, statins cause mild elevation of high density lipoprotein (HDL) concentration, but the mechanism responsible for this effect of statins on HDL metabolism is not well understood. It has been hypothesized that statins affect the HDL level through inhibition of cholesteryl ester transfer protein activity or by stimulating apolipoprotein A-I synthesis. Increased cholesterol efflux from liver due to raised expression of the ABCA1 transporter may also elevate HDL levels. Whereas raising the plasma HDL-C concentration may contribute to the atheroprotective effect of statins, its magnitude is uncertain and additional mechanisms that improve the functionality of HDL may be equally or more important. In this review we analyze what is currently known about effect of statins on HDL metabolism and on reverse cholesterol transport in particular.

Protozoan tropical diseases cause great suffering throughout developing countries, with high rates of morbidity and mortality. American Trypanosomiasis affects 16-18 million people in Latin America, representing a dramatic disease among symptomatic patients. Old, toxic and ineffective chemotherapeutic agents continue to be used for the treatment of Chagas' disease. Since the early days of medicine, chemical substances derived from plants and animals have been used to treat human diseases. In the marine ecosystem ecological pressures, such as competition for space and predation, may have favored several invertebrate organisms to select unique metabolites with an assortment of astonishing biological activities. In terrestrial ecosystems, amphibians present a unique efficient skin secretion system with a variety of glands which produce a myriad of potent bioactive compounds such as peptides, alkaloids, biogenic amines and lipids. Plants contribute with several antitrypanosomal compounds derived mainly from their secondary metabolism. Proteins and peptides from snake venoms have also been considered as novel drug candidates, showing effective activities. In this review, we broadly discuss the epidemiology, pathology, and current treatment of Chagas' disease as well as the contributions of pharmacologically tested marine invertebrate, amphibian, snake and plant compounds which have shown promising antitrypanosomal activities. We also explore these possibilities for developing new chemotherapeutics against Chagas' disease.

Accelerated atherosclerosis and microvascular complications are perhaps the leading cause of coronary heart disease, blindness and renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Several mechanisms including endothelial cell damage, platelet activation and aggregation, hypercoagulability, and impaired fibrinolysis are involved in the pathogenesis of thrombogenic diathesis in diabetes. However, the underlying molecular mechanism is not fully elucidated. A recent clinical study, the Diabetes Control and Complications Trial- Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that the reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persist for at least several years, despite increasing hyperglycemia. In addition, intensive therapy during the DCCT also reduced the risk of cardiovascular events by about 50 % in type 1 diabetic patients 11 years after the end of the trial. These clinical studies strongly suggest that so-called ‘hyperglycemic memory’ causes chronic abnormalities in diabetic vessels that are not easily reversed, even by subsequent, relatively good control of blood glucose. Among various biochemical pathways implicated in diabetic vascular complications, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory ‘hyperglycemic memory’. In this review, we discuss the role of AGEs in thrombogenic abnormalities in diabetes, especially focusing on the deleterious effects of these macroproteins on endothelial cell function, platelet activation and aggregation, coagulation and fibrinolytic systems.

Dopamine receptors have been identified in a number of organs and tissues, which include the central and peripheral nervous systems, various vascular beds, the heart, the gastrointestinal tract, and the kidney. Dopamine receptors are classified into D1- and D2-like subtypes based on their structure and pharmacology; during conditions of moderate sodium balance, more than 50% of renal sodium excretion is regulated by D1-like receptors. Most of the knowledge on the actions of dopamine has been focused on the D1 dopamine receptor. The D5 dopamine receptor also belongs to the D1-like receptor subfamily. Disruption of the D5 receptor results in hypertension. However, unlike the D1 receptor, the hypertension in D5 receptor null mice is caused by the increased activity of the sympathetic nervous system, apparently due to activation of oxytocin, V1 vasopressin, and non-NMDA receptors in the central nervous system. In this paper, we review the physiological action of D5 receptor on the central and peripheral nervous systems, and discuss the possible mechanisms by which hypertension develops when the D5 receptor function is perturbed.