Frontiers in Medicinal Chemistry

Computational screening of compound databases has become increasingly popular in pharmaceutical research. Virtual screening approaches can roughly be divided into target structure-based screening (often referred to as docking) and screening using active compounds as templates (ligand-based virtual screening). Ligand-based screening techniques essentially focus on comparative molecular similarity analysis of compounds with known and unknown activity, regardless of the methods or algorithms used. In this review, we first provide an overview of widely used ligand-based virtual screening approaches including various database filters and then discuss recent trends in this field and new methodological developments.

Coumarins, also known as benzopyrones, are present in remarkable amounts in plants, although their presence has also been detected in microorganisms and animal sources. The structural diversity found in this family of compounds led to the division into different categories, from simple coumarins to many other kinds of policyclic coumarins such as furocoumarins and pyranocoumarins.

Simple coumarins and analogues are a large class of compounds that have attracted their interest for a long time due to their biological activities: they have shown to be useful as antitumoural, anti-HIV agents and as CNS-active compounds. Furthermore they have been reported to have multiple biological activities (anticoagulant, anti-inflammatory) although all these properties have not been evaluated systematically. In addition their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics of this field of research.

The present work is to survey the information published from 1990 till 2008, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues such as biscoumarins and triscoumarins. Information is also highlighted concerning the development of new synthetic strategies that could help in drug design and in the work on SAR or QSAR.

Analytical chemists have increasingly turned their attention to drug discovery and drug analysis and to solve fundamental questions of biological significance in physiology and genetics. New technologies have been developed, and a variety of instruments have been redesigned for biomedical applications. The development of high-performance liquid chromatography (HPLC) opened a new era in biorelated fields and allowed faster separations of fragile macromolecules. Capillary column gas chromatography (GC)/mass spectrometry (MS) have been used to achieve more powerful separation and to perform structural analysis of molecules, and laboratory automation including robotics has become a powerful trend in both analysis and synthesis.

Liquid chromatography (LC)/MS is more suitable for biomedical applications than GC/MS because almost all biomolecules are heat sensitive. Furthermore, a combination of various mass spectrometers has been used even for proteins directly. Improving the sensitivity of nuclear magnetic resonance spectrometry (NMR) has permitted a direct connection with LC. Purification of biomolecules on-line by LC has been performed since the development of chip-electrophoresis. On the other hand, computational chemical analysis is a promising technique given the advancing the hardware and software for use in chemical fields. In this review, a combination of chromatography and computational chemistry for use in drug discovery studies is described. Fast LC analysis using a column switching technique was introduced for aromatic amino acid metabolites and guanidino compounds. Recent developments in related technologies are also included from review papers.

The clinical use of chelating drugs as antidotes for metal toxicity are reviewed, together with the in vivo effects of their synthetic homologues and new chelating agents. Concise facts on toxic effects of human exposure to metals are given for the following elements: lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium, arsenic, chromium, nickel, and platinum. Pharmacokinetic data, clinical use and adverse effects of the majority of chelating drugs used in human metal poisoning, are briefly summarized, i.e. dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-D-penicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), calcium trisodium or zinc trisodium diethylenetriaminepentaacetate (CaNa3DTPA, ZnNa3DTPA), deferoxamine (DFO), deferiprone (L1), deferasirox (ICL670), triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). The in vivo effects of three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA and DTPA), derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA), and carbodithioates, are also described. Among the number of factors that can influence the efficacy of chelation treatment, modifying effects of age are shown, in light of experimental results in young and adult animals.

Taurine was discovered more than two hundred years ago from animal sources. It is distributed in both mammals and non-mammals and its content is high in several tissues. For more than a century-and-a-half, taurine was regarded just as an end product of sulfur metabolism. Recently, taurine has been rediscovered and its beneficial effects in processes like epilepsy, hypertension, congestive heart failure and diabetes have been well-documented. It was patented and found some clinical utility, but being an amino acid, therapeutic use confronts limitations like restricted permeability and more. This necessitates the development of prodrugs (analogues) mainly derivatives of taurine. A large number of taurine derivatives have been reported in the literature with partial to marked activity. Taurine derivatives like taltrimide, acamprosate and tauromustine, are already in the market as anti-convulsant, anti-alcoholic and anti-cancer agents. Many other analogues are effective in experimental models. The in depth analysis of these analogues and their biological actions can provide certain clues for further consideration. In the present review, attempts have been made to provide synopsis, synthesis and symbiosis of chemical and biological actions, which may provide future guidance and facilitate further research in this area. The successful journey of these analogues to clinical utility is a healthy and happy sign and an index of bright future, and we hope that this review will provide enough input to ignite the minds.

Digitalis compounds are used in the treatment of congestive heart failure as positive inotropic agents; their action is mainly due to the inhibition of the Na+,K+-ATPase. A well-known drawback is their arrhythmogenic potential together with a low therapeutic index. Digitalis compounds are characterized by a cis/trans/cis steroidal skeleton with an α,β-unsaturated lactone (γ-butyrolactone) in the 17β-position, a 14β-hydroxy group and a 3β-hydroxy group, the latter usually linked to one or more sugar rings. The first three moieties are considered essential for inotropic activity, while the glycosides are responsible for the pharmacokinetics of the compounds.

This review briefly reports on some of the replacements for the unsaturated γ- butyrolactone moiety and then summarizes the work at Prassis that led to the discovery of the O-aminoalkyloxime group as a very powerful substitute. We also report on the development of new steroidal compounds which act as digitalis-like inhibitors of the Na+,K+-ATPase, without any of the chemical features that are peculiar to naturally occurring digitalis glycosides.

Medicinal compounds from plants represent one of the largest and most diverse groups of plant secondary metabolites. The advent of advanced bioinformatics tools and modern genetic technology allowed for manipulation of biosynthetic pathways with the potential of generating novel chemical entities. First, public databases of secondary metabolite related enzymes were interrogated to identify relevant plant genes from vinca rosea (Catharanthus roseus) and other species. Genes of interest were tested after cloning by transfection into tobacco cell cultures using DNA viral vectors. The biosynthetic enzymes coded by these genes were over-expressed in the host. Automated solvent extraction procedure was employed to extract secondary metabolites from plant leaf tissues and transfected tobacco cell culture samples. The composition of the extracts was analyzed by state of the art bioanalytical methods such as high performance liquid chromatography and capillary electrophoresis to monitor changes in secondary metabolite patterns.

Infectious diseases are a significant cause of morbidity and mortality worldwide, accounting for approximately 50% of all deaths in tropical countries and as much as 20% of deaths in the Americas. Despite the significant progress made in microbiology and the control of microorganisms, sporadic incidents of epidemics due to drug resistant microorganisms and previously unknown diseasecausing microbes pose an enormous threat to public health. These negative health trends call for a global initiative for the development of new strategies for the prevention and treatment of infectious disease. For over 100 years chemical compounds isolated from medicinal plants have served as the models for many clinically proven drugs, and are now being re-assessed as antimicrobial agents. The reasons for the renewed interest in plant-based drugs includes a reduction in the new antibacterial drugs in the pharmaceutical pipeline, an increase in antimicrobial resistance, and the need of treatments for new emerging pathogens. Literally thousands of plant species have been tested against hundreds of bacterial strains in vitro and many medicinal plants are active against a wide range of gram positive and gram-negative bacteria. However, very few of these medicinal plant extracts have been tested in animal or human studies to determine safety and efficacy. This review focuses on the medicinal plants and bacteria for which there is significant published in vitro, in vivo and clinical data available. The examples provided in this review indicate that medicinal plants offer significant potential for the development of novel antibacterial therapies and adjunct treatments (i.e. MDR pump inhibitors).

Quassinoids are highly oxygenated triterpenes, which were isolated as bitter principles from the plants of Simaroubaceae family. Their synthesis has attracted much attention because of the wide spectrum of their biological properties. The most prevalent quassinoids have C-20 picrasane skeleton, some known as bruceolides as they were isolated from the genus Brucea, which showed marked antileukemic and antimalarial activities.

The use of plant extracts and isolated chemical compounds as antidotes against snake venoms is a common practice in places where a prompt access to serum therapy is lacking. Although there are a number of reports on plants from different geographical areas that are able to neutralize snake venoms, only a few chemical compounds have been isolated and identified as active components. In reviewing this area of research, it can be concluded that many plants recorded in popular use as anti-snake venoms may display antidotal properties due to the great number of active compounds they contain. However, it is also clear that not all claims of antidote effects towards snake venoms are warranted. In addition, biotechnological application of these inhibitors, as helpful alternative or supplemental treatments serum therapy, and also as important models for synthesis of new drugs of medical interest, needs to be better oriented and scientifically explored.

Loss of normal cell cycle regulation is the hallmark of human cancers, and alteration of the components involved in cell cycle regulation occurs in most human tumors. This suggests that Cyclin dependent kinases (CDKs) are an attractive target for the development of pharmacological agents for the treatment of cancer. Recently, CDK family members that are not directly involved in cell cycle regulation have been identified. This includes CDK7, CDK8, and CDK9, which participate in transcription regulation, and CDK5, which plays a role in neuronal and secretory functions. Given the involvement of CDKs in multiple cellular processes, development of selective small molecule inhibitors for specific CDKs is expected to help clarify whether improved specificity of cell cycle CDK inhibitors will enhance their therapeutic potential in cancer treatment. Selective inhibitors are also needed as tools to explore the biology of diseases in which CDKs may participate and to help develop therapeutics to treat them. Intensive screening and drug design based on CDK/inhibitor co-crystal structure and SAR studies have led to the identification of a large variety of chemical inhibitors of CDKs. Although they are competitive with ATP at the catalytic site, their kinase selectivity varies greatly, and inhibitors selective for certain CDKs have begun to be identified. There are currently two categories of selective CDK inhibitors: those that are selective for CDK2 and CDK1 and those that are selective for CDK4/6. These two types of inhibitors have different effects on tumor cells and are expected to be useful in the treatment of cancer.

Protein tyrosine phosphatase (PTP) is the family of enzymes that are key players in cellular signal transduction system and perturbation in their functioning is implicated in many disease-states. Diverse chemical compounds are being synthesized and evaluated as PTP inhibitors. This review presents a brief account of various enzymes of the PTP family and their inhibitors. Peculiar features of these enzymes and their roles in various diseases are summarized along with important inhibitors developed in recent years.

The matrix metalloproteinases (MMPs) are a family of more than 20 enzymes that are intimately involved in tissue remodeling. These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenase, stromelysins and gelatinases and are involved in the degradation of the extracellullar matrix (ECM) that forms the connective material between cells and around tissues. Disease processes associated with the MMPs are generally related to imbalance between the inhibition and activation of MMPs resulting in excessive degradation of the ECM. These indications include osteoarthritis, rheumatoid arthritis, tumor metastasis, and congestive heart failure.

Inhibitors for these enzymes have been developed for the treatment of a starthingly wide array of disease process where matrix remodeling plays a key role. There are three major components to most MMP inhibitors - the zinc binding group ZBG, the peptidic backbone and the pocket occupying side chain. Most MMPs inhibitors are classified according to their ZBG. Inhibitors interactions at active-site zinc play a critical role in defining the binding mode and relative inhibitor potency. The majority of MMP inhibitors reported in the literature, contains an effective zinc binding group (e.g. hydroxamic acid, carboxylic acid, sulfhydryl group) that is either generally substituted with a peptide-like structure that mimics the substrates that they cleave or appended to smaller side chains that may interact with specific subsites (e.g., P1', P2', P3') within the active site.

Although carboxylates exhibit weaker zinc binding properties than hydroxamates, they are known to show better oral bioavailability and are less prone to metabolic degradation. The expected loss of binding affinity after replacement of hydroxamates against carboxylates is faced by adequate choice of elongated S1' directed substituents.

The need for novel selective MMP inhibitors makes them an attractive target for the QSAR and molecular modeling. 3-D QSAR models were derived using CoMFA, CoMSIA and GRID approaches leading to the identification of binding regions where steric, electronic or hydrophobic effects are important for affinity.

Some structural requirements essential for achieving high binding affinity and selectivity are: an acidic unit tightly anchored through four contact points, bidentate chelation of Zn2+, carbonyl groups for hydrogen bonding, more than two extra units for hydrogen bonds, a hydrophobic moiety.

Helicobacter pylori is one of the most common pathogenic bacterial infections, colonising an estimated half of all humans. It is associated with the development of serious gastroduodenal disease - including peptic ulcers, gastric lymphoma and acute chronic gastritis. Current recommended regimes are not wholly effective and patient compliance, side-effects and bacterial resistance can be problematic. Drug delivery to the site of residence in the gastric mucosa may improve efficacy of the current and emerging treatments. Gastric retentive delivery systems potentially allow increased penetration of the mucus layer and therefore increased drug concentration at the site of action. Proposed gastric retentive systems for the enhancement of local drug delivery include floating systems, expandable or swellable systems and bioadhesive systems. Generally, problems with these formulations are lack of specificity, limited to mucus turnover or failure to persist in the stomach. Gastric mucoadhesive systems are hailed as a promising technology to address this issue, penetrating the mucus layer and prolonging activity at the mucus- epithelial interface. This review appraises gastric retentive delivery strategies specifically with regard to their application as a delivery system to target Helicobacter.

As drug-resistant strains emerge, the development of a vaccine to eradicate and prevent reinfection is an attractive proposition. Proposed prophylactic and therapeutic vaccines have been delivered using a number of mucosal routes using viral and non-viral vectors. The delivery form, inclusion of adjuvants, and delivery regime will influence the immune response generated.

Since 1996, highly active antiretroviral therapy (HAART) was designed to rapidly control HIV replication. It has had a significant impact on patient health and progression of AIDS in developed countries, but its success has not been complete. HAART strategy still suffers from issues of patient compliance, cost, deleterious side effects and emerging drug resistance. Therefore, expansion of novel anti-HIV drugs and targets will be critical in the coming years. In this context, discovering anti-HIV agents from natural sources and particularly from plants may highlight the principle of a nutritional antioxidant antiretroviral diet. In this paper, we review the putative anti-HIV activity of simple caffeic acid derivatives, together with their antioxidant properties. Toxicity, metabolism and bioavailability, when known, will also be detailed. Well-known caffeic acid derivatives, such as chicoric, rosmarinic and lithospermic acids, may be designed as future leads multitarget anti-HIV compounds and the plants and vegetables containing them as potent nutritional therapeutic supplementation source. They are not expected to replace the actual antiretroviral therapy, but more likely, to complete and perhaps lighten it by adapted diet.

Tuberculosis (TB) is one of the most devastating diseases primarily due to several decades of neglect and presents a global health threat of escalating proportions. TB is second leading infectious cause of mortality today behind only HIV/AIDS. The impetus for developing new structural classes of anti-TB drugs comes from the emergence of multi drug-resistant (MDR) strains to commonly used drugs, substantially longer durations of therapy that are needed because of resistance, and the resurgence of disease in immuno-compromised patients. Recent years have witnessed emergence of many new structural classes of anti-TB agents, which have exhibited promising activities against drug-sensitive and drug-resistant strains of the causative organism Mycobacterium tuberculosis. These analogues ideally should decrease the overall duration of therapy with improved efficacy, and exhibit mechanisms of action different from those of existing drugs to counter the resistant strains of M. tuberculosis. This review provides a comprehensive literature compilation on advances in the new structural classes of anti-TB analogues reported during the past eight years. Our discussion and observations are concentrated on chemotherapeutic potential of thirty-eight new structural classes of anti- TB agents that includes:- acetamides, 5-arylidene-2-thiohydantoins, benzoxazoles and benzothiazoles, benzoic acid hydrazones, benzoxazines, carbohydrates, chalcones, coumarins, deazapteridines, imidazoles, indoloquinazolinones, isothiosemicarbazones, mycobactins, 1,8-naphthyridines, phenazines, diaryl ethers, hydroxamic acids, nitrofurans, N-substituted amino acids, purines, pyridines, pyrimidines and thymidines, pyrroles, phenothiazines, pyrazoles, pyrrolidine carboxamides, quinolines, quinoxalines, isoxazoles, diarylmethanes, taxanes, thioureas, terpenes, thiadiazine thiones, thiolactomycins, adenosines, toludines, and triazoles.

Immune responses to cancer cells can be elicited in vivo by administering synthetic peptides derived from proteins uniquely or overexpressed on tumor cells (tumor associated antigens - TAAs). Peptides derived from TAAs are presented in the context of major histocompatibility complex (MHC) molecules to cytotoxic T cells (CTL), which can recognize and lyze tumor cells. In contrast to peptides derived from an exogenous source (viral or bacterial), tumor peptides bind weakly to MHC class I molecules. The low binding affinity of these peptides makes them poor candidates for vaccination due to the poor immunogenic response produced. In order to enhance antigen recognition and hence immunogenicity, peptide binding affinity for MHC can be initially improved by modifying the 'anchor' residues. However, the task at hand is highly unpredictable and minor changes in peptide sequence can alter/abolish the T cell response. Furthermore, despite the wealth of information obtained over the last decade from high resolution X-ray structures of MHC class I in complex with peptides (pMHC) as well as pMHC in complex with T cell receptor (TCR), prediction remains difficult. Nonetheless, peptides represent convenient chemical entities that can be rapidly synthesized in clinical grade for therapeutic applications. Herein, the rationale behind modifying TAAs will be discussed including the synthesis/use of proteolytically tolerant peptides (and peptide mimetics) which incorporate non-natural amino acids, retro-inversion and cyclization to improve bioavailability.

Telomerase is a ribonucleoprotein polymerase that maintains the length of telomeric DNA by adding hexameric units (TTAGGG) to the ends of the chromosomes. This mechanism prevents replicative senescence, thus conferring unlimited proliferative potential to cells. Telomerase reactivation has been detected in most human tumour tissue, indicating that the enzyme may be useful as a specific tumour marker. The inhibition of telomerase causes a progressive and critical reduction of telomeres, leading to a potent signal for the blockage of cell proliferation and the induction of apoptosis. Since normal somatic cells lack telomerase activity, the anti-telomerase approach is highly specific for tumour cells and metastases. Prolonged treatment is required before enzyme deactivation causes the telomeres to be shortened enough to induce senescence and apoptosis. Therefore, the drugs employed in anti-telomerase therapy should be of only moderate nonspecific cytotoxicity. Certain cis-Pt(II)-complexes have recently been shown to be effective inhibitors of telomerase in both cell-free and in vitro assays, most likely by targeting the nucleobases of the RNA component of the enzyme.

The αvβ3 receptors which are members of the group of the cellular adhesion molecules (CAM), are heterodimeric transmembrane glycoprotein receptors involved in processes such as cell-cell and cell-matrix adhesion, cell migration and signalling.

Integrin αvβ3 receptor is expressed on almost cells originating from the mesenchime and seems to mediate several biological processes, including adhesion of osteoblasts to the bone matrix, migration of vascular smooth muscle cells, and angiogenesis.

Many efforts were done in the last 15 years in order to individuate inhibitors for αvβ3 receptors, due to their involvement in important pathophysiological functions. In fact, selective αvβ3 antagonists offer new therapeutic opportunities for the treatment of several human pathologies like osteoporosis, restenosis and diseases involving neovascularization such as rheumatoid arthritis, tumour induced angiogenesis and methastasis. Purpose of this account is to summarize the recent developments in the field of non peptidic αvβ3 antagonists.

A number of histone deacetylase (HDAC) inhibitors have been developed as anticancer agents and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA), Trichostatin A (TSA) and NVPLAQ824. However, hydroxamic acids have been associated with poor pharmacokinetics and severe toxicity. In addition, although isozyme-selective HDAC inhibitors are considered useful not only as tools for probing the biology of an enzyme but as drugs with low toxicity, many of the hydroxamate HDAC inhibitors do not distinguish well among the HDAC isozymes. Thus, there has been considerable interest in developing non-hydroxamate HDAC inhibitors. To date, small fatty acids, o-aminoanilides, electrophilic ketones, N-formyl hydroxylamines, thiols and mercaptoamides have been reported as non-hydroxamate HDAC inhibitors, and some of them show antiproliferative activity comparable to hydroxamates. Interestingly, hydroxamate HDAC inhibitors such as SAHA and TSA do not discriminate well among the HDAC isozymes whereas many non-hydroxamate HDAC inhibitors have shown selectivity. These non-hydroxamate HDAC inhibitors should pave the way for the development of tools for biological research and new medicines with few side effects. In this review, we introduce nonhydroxamate HDAC inhibitors describing their design, enzyme inhibition, cancer cell growth inhibition and isozyme selectivity.

The treatment of dyslipoproteinemia has proven a successful strategy in the prevention of cardiovascular diseases. The major target of hypolipidemic drugs is the reduction of low density lipoprotein cholesterol (LDL-C). HMG-CoA reductase inhibitors (HMGRI) effectively lower LDL-C by inhibiting the mevalonate pathway and enhancing the activity of the LDL receptor (LDL-R). Numerous clinical studies demonstrated convincingly, that the reduction of LDL-C lowers the incidence of cardiovascular events in primary and secondary prevention. Two new HMGRI, rosuvastatin and pitavastatin, have been evaluated in clinical trials. Both drugs demonstrated efficacy in lowering atherogenic lipoproteins. In addition to the reduction of LDL-C, they may have a higher potency to lower triacylglycerides (TG) and to increase HDL cholesterol (HDL-C) compared to currently available HMGRI. Other therapeutic strategies examined in experimental animals are the inhibition of squalene synthase, the first enzyme of the mevalonate pathway which is specifically committed to cholesterol biosynthesis, the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the direct up-regulation of LDL receptor activity. The latter compounds, the SCAP ligands, are the first members of a new class of hypolipidemic agents affecting the transcriptional regulation of genes involved in lipid metabolism. Recent treatment guidelines recommend aggressive LDL-C reduction and emphasise the importance of modifying lipid metabolism beyond lowering LDL-C, mainly by lowering TG and raising HDL-C. Although these actions are not primary targets of the compounds discussed here, it is interesting that drugs inducing the LDL-R usually also lower TG and, in the case of HMGRI, increase HDL-C.

During the development of new nonsteroidal anti-inflammatory agents, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB1) receptor. This has led to the development of over 100 cannabimimetic aminoalkylindoles, and the development of SAR for these compounds. Later work demonstrated that the aminoalkyl moiety was not necessary, and could be replaced by a four- to six-membered alkyl chain without loss of affinity. Investigation of these indoles led to the discovery of a CB2 selective ligand, 3- (1-naphthoyl)-N-propylindole. Subsequent work has provided several additional CB2 selective indoles. On the basis of a proposed pharmacophore for the cannabimimetic indoles, a series of pyrroles and indenes were developed, some of which are potent cannabinoids. SAR for several series of pyrroles have been developed. Two groups have described cannabimimetic indenes, which have been employed as rigid models for the receptor interactions of cannabimimetic indoles with the CB1 receptor. There is some evidence that the indoles bind to a somewhat different site on the receptor than traditional cannabinoids, and interact with the receptor primarily by aromatic stacking.

It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. While corticosteroids remain the most important anti-inflammatory treatment for asthma they are rather non-specific in their actions. Their use also raises concerns over side effects and compliance issues, particularly in children and adolescents. There is therefore much effort being made to develop novel more specific and safer therapy for asthma. Efforts are being made to improve existing drugs together with the use of combination therapy with antihistamines and leukotriene antagonists. An important area for potential advances in glucocorticoid (GC) development include the elucidation of the crystal structure of the GC receptor ligand-binding domain that may provide vital information in dissociating the anti-inflammatory effects of GCs from unwanted side-effects. Other areas include the development of humanised monoclonal antibodies for asthma therapy including those against IgE, IL-4 and IL-5 together with the inhibition of adhesion pathways and/or chemokines responsible for inflammatory cell accumulation in the asthmatic lung. The potential for immunotherapy using T cell peptide epitopes or DNA-based vaccines and the use of anti-inflammatory cytokines such as IL-10 or IFN-γ are discussed. Several avenues of research are currently underway in an attempt to define mechanisms by which pro-inflammatory cells such as eosinophils can be safely removed from the asthmatic lung through apoptosis induction and their subsequent ingestion by phagocytes. Novel strategies include elucidation of the intracellular pathways controlling granulocyte apoptosis and the receptor mediated events employed by macrophages and bronchial epithelial cells in the recognition and removal of apoptotic cellular corpses. This paper will provide an overview of both the potential and shortcomings of these diverse approaches to drug development for asthma.

Drugs to treat inflammation are discussed under the following headings: (1) random discoveries covering copper, salicylates, heterocyclic diones, ACTH, adrenal steroids and disease-modifying agents (DMARDs); these include Au(I)- thiolates, chloroquine, and hydroxychloroquine, minocycline, cyclosporin, salazopyrine, D-penicillamine and methotrexate; (2) programmed NSAID developments covering salicylates and fenamates, arylalkanoates, diones, non-acidic NSAIDs, clozic, lobenzarit and coxibs; (3) synthetic glucocorticosteroids; and (4) 'Biologicals' for neutralising pro-inflammatory cytokines. Clinical problems are highlighted, particularly unacceptable side-effects affecting the GI tract, skin, liver, etc. that caused many drugs to be withdrawn. Drug combinations may overcome some of these problems. The bibliography has selected reviews and monographs covering 50 years of publications.

The exact cause of Alzheimer ’ s disease is still unknown; despite the dramatic progress in understanding. Most gene mutations associated with Alzheimer's disease point to the amyloid precursor protein and amyloid β. The α-, β- and γ-secretases execute the amyloid precursor protein processing. Significant progress has been made in the selective inhibition and modulation of these proteases, regardless of the availability of structural information. Peptidic and nonpeptidic leads were identified and several drug candidates are 2008 in clinical trials. Successful trials demand either large cohorts or reliable biological surrogate markers for Alzheimer's disease. Therefore, several radio markers are under investigation to support such clinical trials by PET-imaging. Here we summarize the developments until 2006 and highlight the important developments until 2008.

Collective efforts of academic and industrial research groups have produced great potential for progressively better therapies in treating those afflicted with Alzheimer disease. While dramatic insights have been made regarding the cellular and molecular basis of AD, such mechanistic understanding is incomplete. The neuropathological hallmarks of AD are insufficient markers of early pathological mechanisms and serve poorly as clinical correlates of cognitive function and outcome. Accumulated research indicates that multiple factors are necessary to establish clinical manifestations of AD and dementia identifying AD as a multifactorial disease state where one specific treatment may not prevent or reverse the disease. Appropriately therapeutic targets are not limited to those mechanisms directly identified in generation of these hallmarks but address targets known to impact cognition and neuronal integrity. Successful treatment and evaluation of viable therapies includes co-administration during aging and disease since monotherapy may fail to result in the global suppression of AD. In this review, drug targets and therapeutics will be discussed with specific attention to therapeutic efficacy and new modalities for administration.

Hydroxyurea has emerged as a new therapy for sickle cell disease but a complete mechanistic description of its beneficial actions does not exist. Patients taking hydroxyurea show evidence for the in vivo conversion of hydroxyurea to nitric oxide (NO), which also has drawn interest as a sickle cell disease treatment. While the chemical oxidation of hydroxyurea produces NO or NO-related products, NO formation from the reactions of hydroxyurea and hemoglobin do not occur fast enough to account for the observed increases in patients taking hydroxyurea. Both horseradish peroxidase and catalase catalyze the rapid formation of nitric oxide and nitroxyl (HNO) from hydroxyurea. In these reactions, hydroxyurea is converted to an acyl nitroso species that hydrolyzes to form HNO. The ferric heme protein then oxidizes HNO to NO that combines with the heme iron to form a ferrous-NO complex that may act as an NO donor. In general, acyl nitroso compounds, regardless of the method of their preparation, hydrolyze to form HNO and the corresponding carboxylic acid derivative. Similarly, the incubation of blood and hydroxyurea with urease rapidly form NO-related species suggesting the initial urease-mediated hydrolysis of hydroxyurea to hydroxylamine, which then reacts quickly with hemoglobin to form these products. These studies present two NO releasing mechanisms from hydroxyurea that are kinetically competent with clinical observations.

The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. This review describes new anticonvulsant agents representing various structures for which the precise mechanism of action is still not known. Many of the compounds presented in this review have been tested according to the procedure established by the Antiepileptic Drug Development Program of the Epilepsy Branch of the National Institute of Neurological Disorders and Stroke, National Institute of Health, USA. This review is updating paper published in Current Topics in Medicinal Chemistry (B. Malawska, 2005, 5, 69-85). The newer agents include sulfonamides, sulfamides, amino acids, amides (analogs of γ-vinyl GABA, Nbenzylamides, 2,6-dimethylanilides, carboxyamides, hydroxyamides, acetamides, butanamides, alkanoamides); heterocyclic agents [(arylalkyl)imidazoles, pyrrolidin- 2,5-diones, lactams, semi- and thiosemicarbazones, isoquinolines, thiadiazoles, quinolines, quinolinones, quinazolin-4(3H)-ones, 2,5-disubstituted 1,2,4- thiadia-zoles, xanthones, derivatives of isatin and coumarin] and enaminones. These new structural classes of compounds can prove useful for the design of future targets and development of new drugs.

This review includes the non-patent literature up to August 2008 that deals with selective neuronal nitric oxide synthase inhibitors (highest potency is for the neuronal isozyme). Some non-selective inhibitors or selective inducible nitric oxide synthase inhibitors are mentioned if they are related to compounds that are discussed; structures of these compounds generally are not given. In vitro inhibition constants are given either as IC50 values or as Ki values. An IC50 value, the inhibitor concentration that produces 50% inhibition in the presence of a constant concentration of substrate, is obtained by extrapolation of several rate data points to 50% inhibition. Ki values are derived from several types of plots that relate the concentration of inhibitor with enzyme velocity in the presence of a variety of substrate concentrations [1]. The Ki value can be estimated from the IC50 value [2]. Although the two inhibition constants are related, they are not the same; generally, the reported Ki values tend to be lower than the IC50 values. If specifics are desired about how the data were collected, then the reader will have to look in the literature cited. No attempt was made to be exhaustive in citing all references related to specific inhibitors; rather, examples of literature references are given for each inhibitor described.