Mini Reviews in Medicinal Chemistry - Volume 5, Issue 11, 2005

This review discusses structural aspects of second-generation KATP channel openers (KCOs), which exhibit improved tissue-selectivity. Their therapeutic profile is debated with main focus on cardiac ischemia, asthma, and urinary incontinence.

Cancer remains one of the major causes of death worldwide. Anti-angiogenic therapy is one of the new approaches to anticancer therapy. Out of 22 angiogenesis inhibitors currently under clinical trials there are 11 natural products or were modeled on a natural product parent. This review shows the potential of natural products for the discovery of new anti-angiogenic leads.

Vanadate can be bioequivalent to phosphate and replace it in cellular metabolism. The detection of insulin-like activity has spurred interest in the development of oral anti-diabetic drugs containing vanadium. We collected and evaluated a vast toxicity data set and discussed molecular aspects related to insulin-mimetic effects of vanadium complexes.

The discovery of antibiotics opened a new era in the treatment against several pathogenic microorganisms that can disable or kill humans. The appearance of the fluoroquinolones (based on nalidixic acid, 4-quinolone-3-carboxylates), in the early 1980's, gave a new impetus in the treatment of infectious diseases. Despite these favourable properties, the earlier fluoroquinolones had limited potency against some clinically important organisms, especially Gram-positive pathogens so that the development of resistance to these organisms has become a serious problem. Thus the development of new fluoroquinolones with a better pharmacokinetic profile, potency, broad spectrum of activity, solubility, prolonged serum half-life and oral and parenteral routes of administration has been a major focus on recent research. The increasing interest in this class led me to review the promising new fluoroquinolones in clinical trials.

Type 2 Diabetes Mellitus (DM) or Non-Insulin Dependent Diabetes Mellitus (NIDDM) accounts for 90-95% of all diabetes cases and has become a major health concern over the years. This disease has assumed frightening proportions due to unhealthy food habits and sedentary life style. About a decade ago, due to the absence of defined molecular targets or an understanding of disease pathophysiology, treatment of this disease was mostly focused on insulin secretion or administration of external insulin. During the past decade however, advent of genomics and proteomics has helped in understanding the molecular alteration characteristics of NIDDM. Untreated type 2 diabetes leads to several complications such as hyperlipidemia, hypertension and atherosclerosis - collectively known as Syndrome X. Though United Kingdom Prospective Diabetes Study (UKPDS) showed that normalization of hyperglycemia could prevent majority of diabetes complications, the available treatment regime does not adequately normalize the blood glucose level in type 2 diabetic patients. Currently, four distinct classes of oral hypoglycemic agents are available, some of which can act as lipid lowering agents as well. The efficacy and side effect profiles of these drugs are still to be optimized, so there is an unmet need for better candidates. Several new targets as well as better drugs for old targets are under investigation across the world. Availability of such drugs, based on the validated targets, may lead to a new therapeutic paradigm for the prevention of diabetes as well as complications arising out of it. The current review will deal with existing oral therapies for type 2 diabetes as well as the emerging therapeutic targets.

In this short review the methods of preparation of novel 1,2,4,5-tetraoxacycloalkanes and the related peroxides are summarized, with the emphasis on the usefulness of 1,1-bishydroperoxides as the precursor. Also, their antimalarial activities in vitro and in vivo are discussed.

Virtual screening encompasses several computational approaches which have proven valuable for identifying novel leads. These approaches rely on available information. Herein, we review recent successful applications of virtual screening. The extension of virtual screening methodologies to target families is also briefly discussed.