Current Medicinal Chemistry - Volume 16, Issue 29, 2009

Numerous cellular pathways have a significant impact in the growth and metastatic potential of tumors. Essential element of such pathways is the epidermal growth factor receptor (EGFR), a member of the HER family of receptor tyrosine kinases. One of the most important issues in cancer, which attracted the attention of clinical oncologists, is the potential use of targeted therapies. EGFR signaling pathway is implicated in the control of cell survival, proliferation, metastasis and angiogenesis. EGFR is, therefore, an appealing target for molecular-targeted cancer therapy as it is expressed in a variety of solid tumors (colorectal, breast, head and neck, etc.). Receptor antagonists that target EGFR have already been of high interest for a number of years. Multiple therapeutic strategies have been developed to target EGFR, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), ligand-toxin conjugates, and antisense oligonucleotides. In particular, mAbs block ligand from binding to the extracellular domain of the receptor. Two mAbs that block EGFR (erbB1), cetuximab and panitumumab, have been approved by FDA. Cetuximab is a chimeric IgG1 anti-EGFR monoclonal antibody, whereas panitumumab is a fully human IgG2 anti-EGFR monoclonal antibody. This review highlights the cellular effects of EGFR blockade by mAbs and their relationship to therapeutic efficacy and biological significance.

The matrix metalloproteinases are a family of nearly 30 enzymes that are intimately involved in tissue remodeling. Disease processes associated with the matrix metalloproteinases are generally related to imbalance between the inhibition and activation of matrix metalloproteinases resulting in excessive degradation of the extracellullar matrix. These include osteoarthritis, rheumatoid arthritis, tumor metastasis and congestive heart failure. Despite massive research and development efforts, there are only two drugs launched on the market: periostat (doxycycline), a tetracycline used for periodontal disease and glucosemine sulfate, for osteoarthritis. Possible reasons for the low success rate of matrix metalloproteinase inhibitors in the clinic are mainly from unwanted side effects caused by their lack of selectivity, since inhibition of collagenase-1 may be responsible for the musculoskeletal side effects observed clinically with broad-spectrum inhibitors. Considering these data, many efforts were directed to developing a more selective second generation of inhibitors against the specific matrix metalloproteinases believed to be involved in the different pathologies. This review mainly focuses on selective matrix metalloproteinase inhibitors development on matrix metalloproteinases in terms of antitumor since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, natural products and their derivatives. Through these methods, new hope is emerging in the form of synthetic and natural matrix metalloproteinase inhibitors for the prevention and treatment of cancer.

Despite substantial therapeutic advances, heart failure remains a syndrome associated with high morbidity and mortality. The management of heart failure remains challenging despite the recent different therapeutic advances. The emergence of cardiac biomarkers as increasingly effective clinical tools suggests the potential of a new approach to the management of patients with heart failure. A variety of circulating biomarkers of diagnostic and prognostic utility in heart failure is currently being studied in preclinical, observational and randomized prospective studies. Of the various candidate biomarkers, the greatest wealth of knowledge and clinical experience lies with the B-type naturetic peptides. However, because individual biomarkers may have limited sensitivity and specificity, a multi-marker approach, using combinations of different biomarkers that reflect different aspects of the pathophysiological milieu, would contribute to better risk stratification and optimization of therapy.

The renin-angiotensin system (RAS) plays an important role in the homeostasis of the cardiovascular system and in the development of cardiovascular diseases. An abnormal expression or over activation of the local RAS in the heart and vasculature system is one of the most common mechanisms in pathophysiological processes in cardiovascular diseases. This also provides a basis for medical prevention and treatments using chemical approaches. Losartan is a selective nonpeptite antagonist against type 1 angiotensin II receptors (AT1R), and has been applied in medical treatments of a variety of cardiovascular diseases, including essential hypertension. This article reviews direct and indirect cardiovascular effects of losartan on the heart and blood vessels. It summarizes the chemical basis of AT1R for the action site of losartan, focuses on the mechanisms underlying the action of losartan involved in both the heart and vasculature, and reviews the information that may be helpful in the development of new chemical candidates or approaches in the war against cardiovascular diseases.

Type 2 Diabetes (T2D), characterized by elevated levels of blood glucose is a complex disease mainly caused by defects in hepatic glucose balance and the failure of pancreatic β-cells to secrete enough insulin to overcome insulin resistance. Glucokinase (GK) is a member of hexokinase family of enzymes that are responsible for the phosphorylation of glucose to glucose-6-phosphate for further utilization in cells. It plays a key role in glucose homeostasis in cells that express this enzyme, such as β-cells and hepatocytes. It promotes glycogen synthesis in the liver and glucose-sensitive insulin release in the β-cell. While hypoglycemia due to the increased insulin secretion could be a potential concern it was hypothesized that a GK activator with optimized properties would be able to both blunt the postprandial glucose excursion and lower the fasting blood glucose in T2D patients. As a result of intensive medicinal chemistry efforts a number of small molecules have been discovered as GK activators many of which showed antidiabetic effects in animal models of T2D. Some of these activators have advanced into human clinical studies. With the promising preclinical data in hand, GK activators represent a promising and new treatment option for T2D.

Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as local regulator in airway inflammation and pulmonary diseases. The notion that increased adenosine concentrations are associated with lung inflammation indicates the importance of this signaling pathway, which involves the activation of a family of cell surface G-protein coupled receptor subtypes named as A1, A2A, A2B and A3. Recently, important progress has been made to better clarify the role of these receptors in a variety of inflammatory airway disorders including asthma. As a consequence, new molecules with high affinity and high selectivity for the human adenosine receptors subtypes designed to control the airway inflammatory component of asthma have been launched and are currently tested in clinical trials as anti-asthma treatments. With the availability of these molecules for testing in humans, the role of adenosine receptors in asthma can now be validated.

Nuclear steroid receptors (NSR) are ligand-activated transcription factors that play a key role in a variety of vital physiological phenomena including developmental or endocrine signaling, reproduction, and homeostasis. In addition, they are implicated in other important biological processes, such as apoptosis. Modulation of apoptosis by NSR is mostly associated with control of pro-apoptotic versus anti-apoptotic gene expression, and includes both induction and prevention of apoptosis depending on cell type. However, it is unclear how NSR can affect opposing expression of the same gene in different cells. Of note, recently described nongenomic mechanisms of NSR, in particular glucocorticoid receptor translocation to mitochondria, were suggested to be crucial steps for triggering apoptosis. NSR often act solely as nuclear transporters of other regulatory molecules, thus indirectly regulating several apoptosis-related genes. Curiously, NSR are thought to cooperate with the anti-apoptotic endogenous bile acid, ursodeoxycholic acid (UDCA), to prevent programmed cell death. In fact, as cholesterol-derived molecules and due to their chemical and structural similarities to steroid hormones, bile acids also modulate NSR activation. Although the precise link between NSR and UDCA remains unclear, we have demonstrated that the bile acid requires NSR for translocation to the cell nucleus as part of a ligand-receptor complex, using a mechanism similar to that of steroid hormones. Interestingly, other studies revealed that UDCA interacts with the glucocorticoid receptor as a novel and selective NSR modifier. The huge diversity of natural ligands and xenobiotics that bind to NSR and regulate their function represents one of the most exciting drug targets for potential therapeutic intervention. The next decade will almost certainly unveil the remarkable role of NSR in modulating cell fate in human health and disease.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). However, to a great extent, the efficacy of NNRTI drugs is impaired by rapid emergence of drug-resistance mutations. Fortunately, detailed analysis of a wide range of crystal structures of HIV-1 RT/NNRTI complexes together with data on drug resistance mutations has identified factors important for design of inhibitors and resilience to mutations, such as, exhibiting conformational flexibility and positional adaptability of NNRTIs, forming extensive main chain hydrogen bonding, targeting highly conserved residues in HIV-1 RT and possessing unconventional mechanisms for NNRTI-mediated inhibition of RT. Besides, the plasticity of NNRTIs binding pocket (NNIBP) also provides a broad space for the discovery of new generations of NNRTIs. For instance, the composite binding pocket, integrating all available crystal structure information about the NNRTI binding site of HIV RT, was demonstrated to be an effective tool to better understand the flexible nature of the binding pocket and to identify specific inhibitors. The RT/solvent interface proved to be an attractive site for incorporating a moiety to improve water solubility and pharmacokinetics or introducing a second pharmacophore to construct multifunctional ligand. Totally, the characterization of NNRTIs and NNIBP may help in the design of more effective drugs that are potent toward wild type and drug-resistant strains of RT. In this paper we attempt to translate the general knowledge gained from a large number of related literature into a set of medicinal chemistry strategies to improve the drug resistance profile of NNRTIs.

In our review entitled ‘Determination of Human Serum α1-Acid Glycoprotein and Albumin Binding of Various Marketed and Preclinical Kinase Inhibitors’ in the Current Medicinal Chemistry, 2009, 16(16), 1964-1977. We wish to correct a research grant number OTKA T049721 in the acknowledgment section. Correct number is OTKA K69213. Acknowledgment section should now be read as: ACKNOWLEDGEMENT This work was supported by the research grants of OTKA K69213, OM-00055/2005, OMFB-00624/2007, OM-00041/2007, OM-00081/2008 and National Office for Research and Technology No. 2006ALAP3-01434/2006. Skilful technical assistance by Ilona Kawka is appreciated.