Mini Reviews in Medicinal Chemistry - Volume 4, Issue 2, 2004

The excitatory neurotransmitter glutamate interacts with ionotropic and metabotropic receptors that mediate a variety of normal signalling processes in the brain. However, excessive stimulation of these receptors appears to be involved in neurodegenerative processes, at least in animal models. Ionotropic glutamate receptors can be divided into NMDA and non-NMDA (AMPA and KA) subtypes on the basis of t heir preferential affinities for the synthetic excitatory aminoacids N-methyl-D-aspartic acid (NMDA) or 2-amino-3- (3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA), respectively. Although most of the early evidence favoured a role for NMDA receptors in the excitotoxic processes, it has been recognised that AMPA receptors may also be significantly involved in neuronal death. As a consequence, the synthesis of specific AMPA antagonists has raised much interest as source of potential drugs for epilepsy and acute and chronic neurodegenerative diseases. The discovery of RPR117824, a potent and selective AMPA receptors antagonist endowed with anticonvulsant and neuroprotective properties, induced growing interest on dihydro-4-oxo-4Himidazo[ 1,2-a]indeno[1,2-e]pyrazine series. This review covers the main chemical course leading to the most promising compounds as well as the pharmacological properties of this original class of AMPA receptor antagonists.

Lysophospholipid analogues (LPAs), originally developed as anti-cancer agents, have shown significant activity against Leishmania spp. and Trypanosoma cruzi, both in vitro and in vivo. Miltefosine, used as a topical formulation (Miltex™) for metastases, was registered in 2002 for the oral treatment of visceral leishmaniasis. LPAs interfere with lipid synthesis in T. cruzi and cancer cells, but the activity is about >20- fold higher against the parasite.

Programmed cell death, or apoptosis, is executed by a series of Cysteine Aspartyl Proteases (Caspases) that form a proteolytic cascade. Each caspase functions either to activate downstream caspases by proteolytic cleavage and / or to proteolytically cleave cellular substrates. Increased levels of apoptosis and caspase activity are frequently observed at sites of cellular damage in both acute (e.g. myocardial infarction, stroke, sepsis) and chronic (e.g. Alzheimer's, Parkinson's and Huntington's Disease) indications. Thus, inhibition of caspase activity with the aim of reducing cell death, and hence tissue damage, is predicted to be therapeutically beneficial. Herein we outline different approaches that have been taken to identify smallmolecule caspase inhibitors that include both traditional (e.g. HTS, structure-based design and substrate analog approaches) and novel screening technologies (e.g. TetheringSM). In addition, the characterization of inhibitors emerging from these programs will also be presented. Many of these compounds demonstrate efficacy in a wide range of animal models; however, only two examples of caspase inhibitors have progressed to clinical testing. Here we will discuss issues (both compound and mechanism related) associated with developing a caspase program in the pharmaceutical industry.

ADME / Tox computational screening is one of the most hot topics of modern drug research. About one half of the potential drug candidates fail because of poor ADME / Tox properties. Since the experimental determination of water solubility is time-consuming also, reliable computational predictions are needed for the pre-selection of acceptable “drug-like” compounds from diverse combinatorial libraries. Recently many successful attempts were made for predicting water solubility of compounds. A comprehensive review of previously developed water solubility calculation methods is presented here, followed by the description of the solubility prediction method designed and used in our laboratory. We have selected carefully 1381 compounds from scientific publications in a unified database and used this dataset in the calculations. The externally validated models were based on calculated descriptors only. The aim of model optimization was to improve repeated evaluations statistics of the predictions and effective descriptor scoring functions were used to facilitate quick generation of multiple linear regression analysis (MLR), partial least squares method (PLS) and artificial neural network (ANN) models with optimal predicting ability. Standard error of prediction of the best model generated with ANN (with 39-7-1 network structure) was 0.72 in logS units while the cross validated squared correlation coefficient (Q2) was better than 0.85. These values give a good chance for successful pre-selection of screening compounds from virtual libraries, based on the predicted water solubility.

This review article deals with the synthesis, physiochemical properties, and potential biomedical applications of two homo-poly amino acids. Poly-α-glutamic acid (α-PGA) and poly-α-lysine (α-PL) were synthesized by chemical synthesis. poly-γ-glutamic acid (γ-PGA) and poly-ε-lysine (ε-PL) were naturally occurring bio-materials that were produced by microbial fermentation. Poly(glutamic acid) (PGA) and poly(lysine) (PL) are water soluble, biodegradable, edible and nontoxic toward humans and the environment. As a result, they are suitable for various applications and have recently attracted considerable interest of the chemical industry. The distinguished features of PGA and PL also make them promising candidates for biomedical applications. The applications of PGA and PL in the areas of biomedical materials, drug delivery carriers and biological adhesives have been studied extensively and will be discussed in this review.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycemic, antithyroid and anticancer activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial antiviral activity in vitro and in vivo. The review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed as effective such agents. Thus, at least some HIV protease inhibitors used clinically (amprenavir) or compounds in advanced clinical trials (tipranavir, TMC- 126, TMC-114, etc.) possess sulfonamide moieties in their molecules, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with less toxicity or activity against drug-resistant viruses. Several non nucleoside HIV reverse transcriptase or HIV integrase inhibitors containing sulfonamido groups were also reported. Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. Most compounds with antiviral activity possessing this mechanism of action incorporate in their molecules primary sulfonamide groups. Finally, some small molecule chemokine antagonists acting as HIV entry inhibitors also possess sulfonamide functionalities in their scaffold.

Helicobacter pylori infection is the major causative factor of a number of gastric pathologies. Several classes of compounds have been identified as anti-H. pylori agents. Here we provide a review of anti-H. pylori compounds that have recently appeared in the literature, including the guanidino, antibiotics, acetamide, pyrazole and benzimidazole compounds.

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. Therefore, it is important to be acquainted with these new structures as well as their syntheses. To these ends, this review covers the syntheses of 28 NCEs marketed in 2002.