Current Medicinal Chemistry - Volume 13, Issue 4, 2006

ATP sensitive potassium (KATP) channels have important functions in neuroendocrine tissue, in smooth and skeletal muscle and in the heart. In pancreatic beta cells the KATP channels, which are formed by 4 ion channels (Kir6.2) and 4 regulatory sulfonylurea receptors (SUR1), control the glucose stimulated release of insulin. The Kir6.2/SUR1 KATP channels are also present in the brain and in other neuroendocrine tissues. Blockers of Kir6.2/SUR1 channels, e.g. glibenclamide and repaglinide stimulate release of insulin and are used for treatment of type 2 diabetes. Openers of Kir6.2/SUR1 channels, e.g. diazoxide, have in contrast only found limited clinical use in treatment of hypersecretion of insulin associated with certain tumours (insulinoma) and genetic disorders (persistent hyperinsulinemia and hypoglycemia of infancy, PHHI). Recent studies have however, indicated that openers of Kir6.2/SUR1 channels could be useful in treatment of e.g. metabolic disorders and diseases of the CNS. The clinical use of diazoxide has been hampered by its lack of potency and selectivity giving rise to side effects, such as oedema and hirsutism and new selective openers of Kir6.2/SUR1 channels have been pursued. This has provided several structurally diverse series, which include 1,2,4- thiadiazine 1,1-dioxide derivatives, like BPDZ 62, BPDZ 73, NNC 55-0462, NNC 55-0118 and NN414, cyanoguanidines, nitropyrazoles and 4-sulfamoylphenylbenzamides. NN414 has been shown to be a potent and Kir6.2/SUR1 selective KATP channels opener, which inhibits glucose stimulated insulin release in vitro and in vivo and which has beneficial effects on glucose homeostasis in preclinical and clinical studies.

Dihydrofolate reductase (DHFR) plays an essential role in cellular biochemistry and has been a wellrecognized drug target for over fifty years. Antifolate inhibitors of DHFR, including clinically used therapeutics such as methotrexate, trimethoprim, and pyrimethamine have been successful as anticancer, antibacterial, antifungal and antiparasitic agents. As resistant strains of these microorganisms evolve and as new disease threats arise, the need for new antifolates that are potent and specific for infectious organisms becomes more pressing. Several new antifolates have been reported over the past decade; many of these are potent against a particular species of DHFR, but achieving the goal of potency and selectivity has proven to be more difficult. This review will describe recent advances in attaining species selectivity in developing new antifolates. Specifically, advances in developing inhibitors against Pneumocystis jirovecii and Plasmodium falciparum, the causative agents in pneumocystis pneumonia and malaria, respectively, will be presented.

In the last decade much attention has been paid to the development of metabolically non-reversible dimeric or hybrid compounds, which combine two structural units of one or two lead compounds of interest for the treatment of Alzheimer's disease. As a consequence of their capability to simultaneously interact with two binding sites of the same biological target (the enzyme acetylcholinesterase in most cases), to expand their interaction in the main binding site of the target molecule, or to interact with two different biological targets of interest in the pathogenesis of the disease, these dimeric or hybrid compounds exhibit an improved pharmacological profile including high affinity interactions, additional non conventional actions or complementary actions, what makes them potential drug candidates for the treatment of Alzheimer's disease. Herein, we review from a structural point of view the main classes of dimeric or hybrid compounds developed for the treatment of Alzheimer's disease, along with the pharmacological profile of the most active compounds.

HeLa cells were named for Henrietta Lacks, who died in 1952 from an infection of a special type of cancer. Margaret Gey, her physician, started working with these cancer cells that are still used for medical research. In the present review, an attempt has been made to collect the data for the effects of different chemicals on HeLa cells and to discuss them by the formulation of a total number of 22 QSAR.

Tubular cell loss is prominent both in acute and chronic renal failure. Apoptosis and its regulatory mechanisms contribute to cell number regulation in the kidney. The potential role of apoptosis ranges from induction and progression to repair of renal injury. However, therapeutic interest has focused in preventing the apoptotic loss of tubular cells that leads to acute and chronic renal failure. Death ligands and receptors, such as tumor necrosis factor and Fas ligand, proapoptotic and antiapoptotic Bcl2 family members and caspases have all been shown to participate in apoptosis regulation in the course of renal cell injury. Nevertheless, the precise role of these proteins is unclear, and the participation of most known apoptosis regulatory proteins has not been studied. We now review the role of apoptosis in renal injury, the potential molecular targets of therapeutic intervention, the therapeutic weapons to modulate the activity of these targets and the few examples of therapeutic intervention on apoptosis, with emphasis in acute renal failure.

Tuberculosis (TB) is a global health problem due to the lack of new drugs in the market and also due to the advent of multidrug resistant strains (MDR). This disease affects around 8 million people and kills almost 3 million people each year and it is estimated that there are 1 billion infected with TB worldwide. Due to this problem fluoroquinolones have attracted much attention as the new class of anti TB drugs due to their fewer toxic side effects, improved pharmacokinetic properties and extensive and potent activity against Grampositive and Gram-negative bacteria, including resistant strains. In this present review we report fluoroquinolones as a promising new class of anti TB.

Leptin was originally identified as an adipocyte-derived cytokine with a key role in the regulation of the energy balance. Subsequent research revealed that leptin's biological action is not restricted to its effects on appetite and food intake, but instead has a much more pleiotropic character. There is now ample evidence that leptin has important functions in reproduction, hematopoiesis, HPA-axis endocrinology and angiogenesis. In this review we have focused on the effects of leptin in the antigen-specific immunity and in the inflammatory effector system.