RICERCA ITALIANA     

DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NEW CARDIOVASCULAR DRUGS

Università degli Studi di Bari

Abstract

The aim of this research project is to study compounds active on the cardiovascular system. The pharmacological classes that will be the object of this research are:
a) antihypertensive drugs acting via interaction with angiothensin receptors and NO release;
b) antiarrhythmic drugs acting on cardiac sodium channels and characterized by a reduced incidence of adverse effects;
c) antiatherosclerotic and anti-thrombotic agents (lipid-regulating agents, platelet aggregation inhibitors, radical scavengers, and inhibitors of myocyte proliferation) mainly targeted to:
c.1 interaction with different PPAR receptors that seem to regulate several cardiovascular disorders;
c.2 inhibition of platelet aggregation and radical production that seem to cause endothelial damages underlying atherosclerosis;
c.3 acyl-CoA: cholesterol acyl transferase (ACAT) inhibition as an alternative treatment for hypercholesterolemia;
d) anti-ischemic drugs acting through
d.1 NO release;
d.2 opening of mitochondrial ATP-sensitive potassium channels (mito-KATP);
d.3 interaction with specific adenosine receptor subtypes. <<<

Principal Investigator

Vincenzo TORTORELLA Università degli Studi di BARI

Research Objectives

Taken together, cardiovascular diseases are the leading cause of death in industrialized countries. Various pharmacological approaches can be pursued for the treatment of these pathologies and, among them, the lowering of hypertension, the control of the causative factors of platelet aggregation at the vascular level and the regulation of the disorders underlying atherosclerosis (dislipidemia and endothelial damage caused by mechanical or chemical insults) are particularly important. In addition, within the class of the cardiovascular drugs, compounds able to regulate cardiac frequency have important applications.
The present project aims to gain new insight into the mode of action of compounds active on the cardiovascular system. Additionally it aims to further optimize the activity/side effects ratio of available drugs and to discover entirely new leads. The national team submitting this proposal is composed of five local research groups (Bari, Chieti, Milano, Pisa, and Torino). The staff engaged in the research is made up of 15 full professors, 7 associate professors and 11 university researchers. Many doctoral and post-doctoral students as well as holders of research grants and fellowships will also be collaborating with the permanent staff. The interdisciplinary nature of this research project requires chemical and biological expertise within the group. It has been possible to satisfy this demand in that some pharmacologists have decided to participate in the project. <<<

Timescale

24 months

National and international background

The national program submitted herein foresees the study of drugs with potential for use in the treatment of cardiovascular pathologies. The subject is of great importance in modern clinical practice, due not only to the frequency of cardiovascular diseases but also for the seriousness of their effects on health. An indication of the level of interest in this field is given by the high percentage of the new chemical entities registered for the treatment of cardiovascular disorders, in relation to the total number of new drugs brought onto the market over the last few years.
During the last few decades, numerous studies have been conducted with the aim of gaining insight into the factors contributing to the development of pathologies such as cerebral stroke and myocardial infarction. Although some of these risk factors (e.g. age, gender) are not amenable to modification, others such as hypertension, dyslipidemia, obesity and diabetes can be modified or controlled by the use of appropriate medication and/or a change in life style. The simultaneous presence of more than one risk factor considerably increases the probability of developing cardiovascular problems, and makes the use of safe and selective drugs an absolute necessity.
At the international level, the four classes of drugs that are the object of this program have been extensively investigated. The members of the research groups participating in the present project are all recognized national experts who have been working in this field in academia for many years.
The following is a summary of the most important topics that will be discussed in the following documents, which also include bibliographical references.
For a more complete picture of the research proposed by the national team as a whole, please see the proposals of the individual research groups.
1) Antihypertensive drugs
Both the probability of contracting cardiovascular diseases and their seriousness are correlated with blood pressure. The control of blood pressure and its modification can be kept under control by drugs with various pharmacological actions. In particular, the research proposed herein will take into account antihypertensive drugs acting both via interaction with angiothensin II receptors, with known implications for the cardiovascular system(1, 2), and via release of nitrogen monoxide. This compound, which is formed due to the action of enzymes that are widely present in the human body, is an extremely important bioregulator implicated in many biological functions (3). In endothelial tissue, the massive presence of enzymatic systems responsible for the formation of NO makes the presence of nitric oxide of great importance for the cardiovascular system. The possibility of designing hybrid drugs with vectors able to free NO, and thus having a further pharmacological action, has already been demonstrated (4, 5).
2) Anti-arrhythmic agents interacting with sodium ion channels (e.g., tocainide and mexiletine, 6-9).
3) Anti-atherosclerotic and anti-thrombotic agents (lipid-regulating agents, platelet aggregation inhibitors, radical scavengers, and inhibitors of myocyte proliferation).
It is well known that chiral derivatives of clofibric acid, an important lipid-regulating agent, show a favourable dissociation of their pharmacological properties (10). In fact, their optical antipodes have the same anti-cholesterolemic activity but a different action in inhibiting platelet aggregation and inducing hepatocarcinogenesis related to the PPAR-alpha receptors (11), as well as a different myotonic action related to the chloride channels. A considerable body of recent research has shown that the effects of fibrates on the metabolism of lipoproteins and lipids are mediated by different PPAR receptors (12,13) and thus that the compounds active on these receptors can, in principle, be useful in combating atherosclerosis.
The platelet aggregation inhibitors include NO-donors (14) and COX inhibitors (15). Molecular hybrids obtained by conjugation of NO-donor moieties with COX inhibitors may be envisaged as new potential anti-atherosclerotic agents.
4) Anti-ischemic drugs.
Recent experimental reports show that the administration of exogenous NO confers an increased resistance of myocardium against ischemic injuries (17). This phenomenon is mediated through the activation of NO-induced intracellular, cGMP-dependent events and the opening of mitochondrial ATP-sensitive potassium channels (mito-KATP)(18). The modulation of these events may represents the rational for the development of innovative anti-ischemic drugs. Finally, given the widespread actions of adenosine in the cardiovascular system, it seems interesting to look for new ligand for adenosine receptor subtypes. In particular, selective A2a and A3 ligands could be useful in ischemia conditions (19) and in the acute treatment of stroke (20). <<<