Current Medicinal Chemistry - Volume 10, Issue 11, 2003

Malaria is a very serious infectious disease against which the currently available drugs are loosing effectiveness. The main problem is the emergence and the spreading of resistant parasite strains. New treatments are needed in order to regain control over the disease. Drug discovery efforts towards this goal are likely to be more successful, if they focus towards novel mechanisms of action. Such efforts will result in drugs that are functionally and structurally different from the existing drugs and therefore will overcome existing resistances. Here we focus on the aspartic protease plasmepsin II, which is a promising new drug target. We review the drug discovery efforts that were published in the literature on this enzyme, and we present the compounds synthesized at Actelion Pharmaceuticals Ltd.

Gene expression, both tissue specific or inducible, is controlled at the level of transcription by various transcription factors interacting with specific sequences of DNA. Anticancer drugs and other potential therapeutic agents alter interactions of regulatory proteins with DNA by a variety of different mechanisms. The main ones, considered in the review, are: i) competition for the transcription factor DNA binding sequences by drugs that interact non-covalently with DNA (e.g. anthracyclines, acridines, actinomycin D, pyrrole antibiotics and their polyamide derivatives); ii) covalent modifications of DNA by alkylating agents (e.g. nitrogen mustards, cisplatin) that prevent transcription factors from recognizing their specific sequences, or that result in multiple “unnatural” binding sites in DNA which hijack the transcription factors, thus decreasing their availability in the nucleus; iii) competition with binding sites on the transcription factors by synthetic oligonucleotides or peptide nucleic acids in an antigene strategy. The latter compounds may also compete for binding sites on regulatory proteins, acting as decoys to lower their active concentration in the cell. In this review, we have summarized recent advances which have been made towards understanding the above mechanisms by which small molecules interfere with the function of transcription factors.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti- carbonic anhydrase, diuretic, hypoglycemic and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial antitumor activity in vitro and in vivo. Although they have a common chemical motif of aromatic / heterocyclic or amino acid sulfonamide, there are a variety of mechanisms of their antitumor action, such as carbonic anhydrase inhibition, cell cycle perturbation in the G1 phase, disruption of microtubule assembly, functional suppression of the transcriptional activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition among others. Some of these compounds selected via elaborate preclinical screenings or obtained through computer-based drug design, are currently being evaluated in clinical trials. The review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed as effective tumor cell growth inhibitors, or for the treatment of different types of cancer. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Thus, at least two clinically used HIV protease inhibitors 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. Some small molecule chemokine antagonists acting as HIV entry inhibitors also possess sulfonamide functionalities in their scaffold.

Pharmacological modulation of serum lipid levels is a powerful means of favourably modifying the risk and incidence of coronary disease. High density lipoproteins (HDL) exert a beneficial influence on atherosclerotic disease, in part by modulating blood lipid metabolism. Three factors have contributed to the growing interest in HDL as a therapeutic target. Firstly, recent, if limited, clinical trials have demonstrated the cardiovascular benefits of modulating HDL. Secondly, on-going studies have clarified several aspects of HDL metabolism and opened new avenues for pharmacological intervention. Thirdly, the WHO foresees an enormous global increase in the incidence of type 2 diabetes, as well as a related disorder, the metabolic syndrome. Both have, as their primary complication, cardiovascular disease whilst one of the principal lipid disorders is a reduction in HDL. Thus for several cogent reasons, HDL has become a primary target for drug development. The review covers our understanding of HDL metabolism, and notably the contribution of recent studies, in the context of potential sites for intervention. The rationale for targeting such sites, and available human and animal data on the cardiovascular consequences of modulating their activities, is discussed. Finally, the current status of drugs developed with a view to influencing HDL metabolism is presented.

Calcium (Ca2+) ions are the currency of heart muscle activity. During excitation-contraction coupling Ca2+ is rapidly cycled between the cytosol (where it activates the myofilaments) and the sarcoplasmic reticulum (SR), the Ca2+ store. These fluxes occur by the transient activity of Ca2+-pumps and -channels. In the failing human heart, changes in activity and expression profile of Ca2+-handling proteins, in particular the SR Ca2+-ATPase (SERCA2a), are thought to cause an overall reduction in the amount of SR-Ca2+ available for contraction. In the steady state, the Ca2+-content of the SR is essentially a balance between Ca2+-uptake via SERCA2a pump and Ca2+-release via the cardiac SR Ca2+-release channel complex (Ryanodine receptor, RyR2). This review discusses current pharmacological options available to enhance cardiac SR Ca2+ content and the implications of this approach as an inotropic therapy in heart failure. Two options are considered: (i) activation of the SERCA2a pump to increase SR Ca2+-uptake, and (ii) reduction of SR Ca2+-leakage through RyR2. RyR2 forms a macromolecular complex with a number of regulatory proteins that either remain permanently bound or that interact in a time- and / or Ca2+-dependant manner. These regulatory proteins can dramatically affect RyR2 function, e.g. over-expression of the accessory protein FK 506-binding protein 12.6 (FKBP12.6) has recently been shown to reduce SR Ca2+-leak.Recent attempts to design positive inotropes for chronic administrations have focussed on the use of phosphodiesterase III inhibitors (PDE III inhibitors). These compounds, which increase intracellular cAMPlevels, have failed in clinical trials. Therefore medical researchers are seeking new drugs that act through alternative pathways. Novel cardiac inotropes targeting SR Ca2+-cycling proteins may have the potential to fill this gap.