Frontiers in Medicinal Chemistry

Integrating physicochemical, absorption, distribution, metabolism, excretion, pharmacokinetics, and toxicity data into the drug discovery/preclinical development decision process in order to reduce the attrition rates of new chemical entities (NCEs) in clinical development is reviewed. The review is organized around the three main stage gates in a small molecule target-based approach including hit-to-lead (H2L), lead optimization (LO) and the final stage gate for selecting NCEs for entry into Phase I clinical trials. The preclinical in silico computational methods and in vitro cellular assays utilized at each stage gate are discussed from a drug discovery perspective. Preclinical assays utilized at the H2L and LO stage gates must have turn-around-times within a timeframe that is consistent with the iterative cycle of the research projects and consume small quantities of compounds while at the final NCE stage gate more traditional assays are used. Unfortunately, many preclinical assays are ambiguous in predicting human preclinical data since they contain a significant amount of falsepositive and false-negative information and, therefore, are not easily translatable from cellular/animals to humans. Thus, understanding the limitations of these preclinical assays is a must for all medicinal chemists for developing go/no-go selection criteria and drug-design optimization strategies to advance small molecule drug candidates through the various stage gates of a target-based screening approach.

Oxidative stress occurs due to the combination of excess reactive oxygen species and insufficient antioxidant capacity. Oxidative stress has been correlated with endothelial dysfunction, the pathogenesis of atherosclerosis as well as with high incidence of cardiovascular disease. A variety of antioxidants has been studied, during the past few years, for the prevention and treatment of atherosclerosis. Early observational studies, focusing on dietary antioxidants, demonstrate an inverse association between antioxidant intake and major cardiovascular events, and supported a number of largescale, randomized, placebo-controlled clinical trials, which investigated the effect of selected antioxidant therapies on primary and secondary cardiovascular prevention. However, the findings appear controversial, since disappointing results have been reported from many studies with little or no decrease in cardiovascular risk while others showed significant reduction of the oxidative stress and improvement of endothelial function. A few rational explanations of these controversial findings have been proposed and should be taken into account in future clinical studies. This chapter provides contemporary data concerning pathophysiology of oxidative stress, its relation to atherogenesis and the potential role of antioxidant therapy in reducing cardiovascular risk via primary and secondary prevention.

Chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions forms an integral part of the development of cardiovascular diseases (CVD), and in particular atherosclerosis. These ROS are released from different sources, such as xanthine oxidase, lipoxygenase, nicotinamide adenine dinucleotide phosphate oxidase, the uncoupling of nitric oxide synthase and, in particular, mitochondria. Endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondriamediated disease processes are not clear, oxidative stress seems to play an important role. In general, ROS are essential to cell function, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects of excessive ROS production. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. This review considers the process of atherosclerosis from a mitochondrial perspective, and assesses strategies for the targeted delivery of antioxidants to mitochondria that are currently under development. We will provide a summary of the following areas: the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as atherosclerosis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondrially-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane in order to protect against mitochondrial oxidative damage, and their therapeutic potential as a treatment for atherosclerosis.

Over recent years, the explosive increase in the worldwide prevalence of type 2 diabetes has transformed this disease into a major public health concern. Cardiovascular complications are the leading causes of morbidity in diabetic patients, whose cardiovascular mortality risk is up to four times higher than in non-diabetic subjects. Morphological and structural changes in large and small vessels are usually preceded by alterations in endothelial function, resulting from the unbalanced production of endothelial-derived vascular mediators. Metabolic disturbances including hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia all contribute to endothelial dysfunction via both distinct and overlapping mechanisms. In turn, abnormal synthesis and release of endothelial mediators may contribute to exacerbate the impaired function of metabolic tissues, thus creating a vicious circle where these conditions reciprocally reinforce and worsen each other. Increasing understanding on mechanisms underlying endothelial dysfunction in diabetes may serve to identify potential therapeutic targets, and help to develop novel therapeutic approaches for reducing cardiovascular risk rate in diabetic patients. This chapter summarizes the current knowledge on the most recently identified targets and therapies for the treatment of diabetes and its cardiovascular complications.

During more than five decades, pyridinium oximes have been developed as therapeutic agents used in the medical treatment of poisoning with organophosphorus compounds. Their mechanism of action is reactivation of acetylcholinesterase (AChE) inhibited by organophosphorus agents. Organophosphorus compounds (OPC) are used as pesticides and developed as warfare nerve agents such as tabun, soman, sarin, VX and others. Exposure to even small amounts of an OPC can be fatal and death is usually caused by respiratory failure resulting from paralysis of the diaphragm and intercostal muscles, depression of the brain respiratory center, bronchospasm, and excessive bronchial secretions. The mechanism of OPC poisoning involves phosphorylation of the serine hydroxyl group at the active site of AChE leading to the inactivation of this essential enzyme, which has an important role in neurotransmission. AChE inhibition results in the accumulation of acetylcholine at cholinergic receptor sites, producing continuous stimulation of cholinergic fibers throughout the central and peripheral nervous systems. Presently, a combination of an antimuscarinic agent, e.g. atropine, AChE reactivator such as one of the standard pyridinium oximes (pralidoxime, trimedoxime, obidoxime, asoxime) and diazepam are used for the treatment of organophosphate poisoning in humans.

Despite enormous efforts devoted to synthesis and development of new pyridinium oximes as potential antidotes against poisoning with OPC, only four compounds are used in human medicine so far. However, they differ in their activity in poisoning with warfare nerve agents and pesticides and there is still no universal broad-spectrum oxime capable of protecting against all known OPC. This article reviews the latest data on structure-activity relationship of pyridinium oximes including their efficacy in treatment of poisoning with organophosphorus compounds.

Application of calixarene derivatives in biotechnology and bio-medical researches is reviewed in this article. Results on antiviral, bactericidal, antithrombothic, antituberculosis, anticancer activities of modified calixarenes are presented. Transfection ability, specific protein complexation, enzyme mimic, membranotropic properties and toxicity of modified calixarenes are described.