Current Pharmaceutical Design - Volume 15, Issue 29, 2009

Non-selective cannabinoid ligands display a wide range of physiological effects including analgesic, antiinflammatory, anti-convulsive and immuno-suppressive activities. A separation between therapeutic effects and undesirable CNS side effects may be accomplished by increasing the selectivity for the CB2 receptor over the CB1 receptor. There is considerable interest in developing new cannabimimetic compounds possessing preferentially high affinity for the CB2 receptor as potential novel therapeutics for the treatment of inflammation and chronic pain. This review will summarize the literature on selective cannabinoid CB2 receptor agonists from 2007 to the present, with special emphasis on SAR and medicinal chemistry strategies to improve physicochemical properties, metabolic stability and oral bioavailabilty of these inherently lipophilic ligands. Incorporating physicochemical property filters early in hit identification, concurrent screening of liver microsomal stability and addressing metabolic hot-spots through structural modifications or bio-isosteric replacements during lead optimization led to a number of structurally diverse CB2 agonists with good oral bioavailability and in vivo efficacy in rodent models of pain.

Atrial fibrillation (AF) following cardiac surgery is a common complication, which increases incidence of other complications, hospital and healthcare costs. The reported rate of the occurrence of postoperative AF varies with different studies, depending on population profile, type of surgery, arrhythmia definition and detection methods, design of study. Nonetheless, the precise mechanisms of AF related to cardiac surgery are poorly understood. A diverse variety of reasons have been proposed for the pathogenesis of this common cardiac arrhythmia. The aim of this review article is to provide an overview of pathophysiological processes that lead to the development of AF post-cardiac surgery. These processes are closely inter-related but the most important ones that have bearing on drug design include the RAAS, ion channels, connexins, fibrosis and extracellular matrix turnover, inflammation and oxidative stress. The autonomic nervous system and structural remodeling all influence all these pathophysiological processes, which should not be viewed in isolation. Understanding such processes would have major implications for the approach to current pharmaceutical design, to improve our approach to drug management strategies.

Frailty is now defined as a clinical entity and potentially responsive to medications. This article reviews the drugs available and those under development. While, at present, exercise is the primary therapy, it is expected over the next decade that numerous drugs will be available to treat components of the frailty syndrome.

Metastases are the cause of 90% of human cancer deaths. The current treatment of cancer with chemo,- and/or radiotherapy is based on cell death by DNA damage neglecting the fact that cancer cell invasion into surrounding tissues and metastasizing are fundamental features of neoplasms and the major reason for treatment failure. Metastasis is the result of several sequential steps and represents a highly organized, non-random, and organ-selective process. A number of in vitro and in vivo models show that tumor cells use chemokine-mediated mechanisms during this metastasizing process, comparable to those observed in the regulation of leukocyte trafficking. Furthermore, chemokines modulate tumor behavior such as the regulation of tumor-associated angiogenesis, activation of host tumor-specific immunological responses, and direct stimulation of tumor cell proliferation in an autocrine fashion. These findings may lead to new drugs that target chemokines or their receptors and will likely be of great additional value for treatment of cancer patients.

Impaired glucose tolerance (IGT) is an independent risk predictor for cardiovascular morbidity and mortality, as well as for total mortality, independent of the subsequent development of overt diabetes mellitus. Increased rates of major adverse cardiac event and shorter survival in subjects with IGT who are post acute myocardial infarction have also been observed. The aim of this review article is to provide an overview of the pathophysiological basis of IGT and the actual mechanism( s) of vascular damage, accounting for its impact in cardiovascular disease (CVD). We focus on endothelial damage, aberrant angiogenesis and apoptosis-the three important pathophysiological mechanisms responsible for most long term complications in frank diabetes. However, on this occasion we evaluate these mechanisms in the milieu of IGT (post prandial hyperglycaemia or post challenge hyperglycaemia) rather than frank diabetes per se. A better understanding of the actual mechanisms of vascular damage in IGT may not only enhance our understanding about the disease process but may also facilitate implementation of appropriate therapeutic measures.

Mast cells, originating from bone marrow pluripotential cells are generally populated near to strategic locations of mammalian body. They store a wide variety of biologically active molecules in their granules and also can de novo synthesize an additional spectrum of mediators, depending on their microenvironment, phenotype and status. Mast cells have numerous receptors that can trigger a wide spectrum of cellular responses, some of them which can be preprogrammed against specific pathogens. Mast cells secrete mediators, go under total degranulation, or degranulate only some of the specific granules with required content according to the environmental conditions, pathogens or signaling molecules binding to their receptors. Mast cells are functionally multi faceted cells. A single cell can behave such as an immune cell, an endocrine cell and even as a sensorial neuron. In this context, mast cells can significantly influence inflammation, tissue remodeling, host defense and homeostasis. Specifically the mast cells proximal to nerve fibers, contain, secrete and respond to, several neuropeptides, suggesting many potential functions for mast cells in health and disease. Mast cells are target cells for neuropeptides and, they have distinct profiles of responsiveness to these molecules. This extends the flexibility of neurogenic signaling pathways via reciprocity. Those neuropeptides have direct and indirect effects on mast cells such as inducing or suppression of degranulation, triggering, modulation or amplification of mediator content and release. The exploration of interactions of mast cells and neurons is a promising field of study which may bring treatments to several diseases. Since mast cells seem to form the major link between neurons and inflammation via neuropeptides, mast cell and mast cell mediator connection may lead to a better understanding of the autocrine, paracrine, and neuro-immuneendocrine systems in physiology and physiopathology. Therefore, mast cell manipulator drug designs, capable of granular content modulation, with effects on, selective mediator release, activity and, ablation of mast cells, would be very beneficial for the treatment of various diseases that mast cells may be involved in.

Metabolic syndrome (MetS) is a cluster of risk factors, each one individually associated with increased cardiovascular disease risk. Treatment of all components of MetS is expected to result in reduced risk. Treatment of MetS mainly includes lifestyle changes. In addition, drug therapy may be considered, especially combinations of different drugs, in order to tackle all the features of MetS. We review the therapeutic strategies currently used for obesity and dyslipidemia treatment in patients with MetS, with a focus on drug combinations.