Mini Reviews in Medicinal Chemistry - Volume 9, Issue 7, 2009

IMiDs compounds are a class of analogues of thalidomide, with greater immunomodulatory activity and a superior safety profile compared to the parent compound. They show substantial increase in potency and an interesting tolerability profile, primarily due to a decreased incidence of the most severe side effect of thalidomide, i.e. Chemotherapy- Induced Peripheral Neurotoxicity (CIPN). These novel aspects of the IMiDs compounds will be discussed.

Neurodegenerative diseases associated with dementia are characterized by cognitive deficits and memory impairment, thus stimulating research for memory enhancing drugs. We survey here the state of the art of research and clinical trials on these drugs from cholinesterase inhibitors and drugs acting on neurotransmitter receptors to drugs acting on gene expression.

The indole scaffold probably represents one of the most important structural subunits for the discovery of new drug candidates. The demonstration that many alkaloids contain the indole nucleus, the recognition of the importance of essential amino acid tryptophan in human nutrition and the discovery of plant hormones served to bring about a massive search on indole chemistry, giving rise to a vast number of biologically active natural and synthetic products, with a wide range of therapeutic targets, such as anti-inflammatories, phosphodiesterase inhibitors, 5-hydroxytryptamine receptor agonists and antagonists, cannabinoid receptors agonists and HMG-CoA reductase inhibitors. Many of these target-receptors belong to the class of GPCRs (integral membrane G-protein coupled receptors) and possess a conserved binding pocket that is recognized by the indole scaffold in a “common” complementary binding domain, explaining the great number of drugs that contain the indole substructure, such as indomethacin, ergotamine, frovatriptan, ondansetron, tadalafil, among many others.

There is compelling evidence that treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors - “statins” - the most important class of lipid lowering agents, reduces ischemic stroke incidence independent on their effect on serum cholesterol levels. In this review, the non-lipid-mediated - “pleiotropic” - effects of statins as well as their potential implication in developing new treatment strategies for stroke prevention will be discussed.

Clofarabine is a second generation of purine nucleoside analogues designed to combine the most favorable pharmacokinetic properties of fludarabine and cladribine. Clofarabine acts by inhibiting DNA polymerases and ribonucleotide reductase as well as by inducing apoptosis in cycling and non-cycling cells. Phase I/II clinical studies revealed its efficacy in hematological malignancies, and in 2004 clofarabine was approved by the United States Food and Drug Administration for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia after at least two prior chemotherapy regimens. The mechanism of action, pharmacology and clinical activity of clofarabine is the subject of this review.

D-Serine, an endogenous modulator of NMDA receptors has been shown to play a vital role in many neuropsychiatric functions such as learning, memory, nociception and implicated in pathological conditions like schizophrenia and Alzheimer's disease. We propose possible therapeutic approaches for some CNS diseases and chronic pain, targeting the D-serine levels by manipulating its uptake, biosynthesis and metabolism.

Bacterial pathogenicity is a result of a combination of factors, including resistance to environmental threats and to the host's defenses, growth capability, localization in the host, tissue specificity, resource obtaining mechanisms and the bacterium's own defenses to aggression. A variety of bacterial components, often specific to each strain, are involved in the microorganism's survival, adhesion and growth in the host. Many of them are harmful and, therefore, are called virulence factors. The effects caused by the virulence factors determine the degree of aggressivity of the strain. In many cases the virulence factors are secreted proteins or enzymes, sometimes performing very specific functions. The enzymatic activity is directed to specific proteins from cell membranes, synaptic vesicle fusion proteins, among other important targets. One of the most toxic bacterial proteins is secreted by Clostridium botulinum, targeted to synaptic vesicle fusion proteins, cleaving them with a zinc-metalloprotease activity, which results in severe neurotoxic effects with a lethal dose as low as eight nanograms per kilogram of body weight. The tetanus neurotoxin acts in a similar way but is less active and Bacillus anthracis also presents a potent metalloprotease activity. In this work we describe a selection of these specially interesting and important bacterial proteins and proteases, stressing their relevance in the pathological process and in medical studies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by pathologic manifestations in multiple organs and elevated morbidity. Traditional management of SLE has included the use of nonsteroidal anti-inflammatory drugs, anti-malarials and immunosuppressive drugs such glucocorticoids, azathioprine, cyclophosphamide, and mycophenolate mofetil. Although many of these therapies have shown great efficacy, they often associate with adverse effects, due to their systemic activity. The development of safer therapies for SLE has led to recent emphasis on targeting selected pathways that can be important in the inflammatory response in SLE. In this context, the use of biological agents such as monoclonal antibodies has seen a rapidly increasing progress, and is poised to be some part of the clinical practice for SLE in a near future. This review provides an update on the ongoing clinical trials and the promise and obstacles in the use of biologics in SLE.

Autoimmune hepatitis (AIH) is a chronic progressive hepatitis, characterized by interface hepatitis with lymphoplasmacellular infiltrates on liver biopsy, high serum globulin level and circulating autoantibodies. It is classified into two types, according to autoantibody profile: type 1 is characterized by anti-nuclear (ANA) and/or anti-smooth muscle (SMA) antibodies; type 2 by anti-liver kidney microsomal type 1 (anti-LKM-1) antibodies. AIH affects all ages, may be asymptomatic, frequently has an acute onset, and can present as fulminant hepatitis. The diagnosis of AIH is based on a scoring system codified by an international consensus. Corticosteroids alone or in conjunction with azathioprine is the treatment of choice in patients with AIH and results in remission induction in over 80% of patients. Alternative proposed strategies in patients who have failed to achieve remission on standard therapy or patients with drug toxicity include the use of cyclosporine, tacrolimus, budesonide or mycophenolate mofetil. Liver transplantation is the treatment of choice in managing decompensated disease, however AIH can recur or develop de novo after liver transplantation.

As the traditional in vivo tests are gradually shifting into in vitro tests, some new issues become apparent. This review discusses the essential considerations in endpoint selection, cell model quality, exposure concentration and linking factors between in vitro and in vivo studies in using in vitro models in risk assessment.

Benzodiazepines are commonly prescribed for the therapy of disorders such as anxiety and sleep disturbance, but develop dependence in many patients. In this review we discuss the impact of different brain areas that modulate the reward system in the development of tolerance and dependence to benzodiazepine and the associative processes underlying those fenomena.

This review presents 201 compounds isolated and identified from plants that present cardioactive activity. These substances have been classified by chemical groups and each provides the most relevant information of its pharmacological activity, action mechanism, chemical structure, spectroscopic date and other properties. Chemical structures have been drawn to indicate the stereochemistry. In this review the summary of the scientific information of plants that present biological activity and the compounds responsible for this activity is presented, which introduces the reader to the study of medicinal plants and also provide bibliographic references, where a detailed study of pharmacology can be found.