Current Topics in Medicinal Chemistry - Volume 11, Issue 12, 2011

The term “metabolic syndrome” refers to a group of abnormalities, including glucose intolerance, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, and hypertension, which collectively constitute the risk factors for cardiovascular disease. Originally coined in the late 1950s, metabolic syndrome has received much attention in recent years as the cardiovascular complications resulted from metabolic disorders Read More

Since Rimonabant was withdrawn in Europe in 2008 because of its substantial CNS risk factors including depression and anxiety, the development of anti-obesity drugs targeting CB1R in the brain has been suspended and/or terminated globally. Instead, developing peripherally restricted CB1R antagonists is actively pursued in the hope that not only could they eliminate any CNS adverse effects observed with Rimonabant, but al Read More

Since the histamine-3 receptor (H3R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experimen Read More

Dipeptidyl peptidase-IV (DPP-IV), a serine protease that specifically cleaves the N-terminal dipeptide with a preference for L-proline or L-alanine at the penultimate position, is involved in the degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 regulates glucose homeostasis by stimulating insulin secretion, inhibiting glucagon release, and d Read More

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the interconversion of inactive cortisone to active cortisol in a NADPH dependent manner. Excess cortisol or 11β-HSD1 leads to insulin resistance and metabolic syndrome. Inhibition of 11β-HSD1 activity has been pursued vigorously by the pharmaceutical industry as a potential therapeutic strategy for the treatment of type 2 diabetes. As a result, a large n Read More

The kidney plays an important role in the regulation of plasma glucose. It is estimated that greater than 99% of the renal glucose filtered by kidney glomerulus is resorbed by sodium-dependent glucose co-transporters (SGLTs), and that SGLT2 located in the proximal renal tubule achieves the most of this assignment. Studies of SGLT2 inhibitors indicate that raising renal glucose excretion by inhibiting SGLT2 helps effectively nor Read More

γ-secretase is an aspartyl protease that cleaves a large number of substrates within the membrane environment. This multiprotein complex is responsible for the last cleavage step of the β-amyloid precursor protein (APP) that generates the amyloid-β peptide (Aβ), one of the primary components of amyloid plaques in Alzheimer's disease (AD). Over the last years, more than 90 type-I membrane proteins have been sh Read More

The use of homology models in docking-based drug discovery is already established, and provides an effective and computationally affordable alternative whenever experimental structures are not available. Recent methodological studies have confirmed and benchmarked the feasibility of using structural models in docking. However, more accurate methods are expected to be developed in the near future, especially for th Read More

Peptide nucleic acids (PNAs) are polyamidic oligonucleotide analogues which have been described for the first time almost twenty years ago and were immediately found to be excellent tool in binding DNA and RNA for diagnostics and gene regulation. Their use as therapeutic agents have been proposed since early studies and recent advancements in cellular delivery systems and in the so called anti-gene strategy make th Read More

According to the β-amyloid (Aβ) hypothesis, compounds that inhibit or modulate γ secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and nontransgenic animal models of AD have indicated that γ secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects o Read More

Aberrant angiogenesis has been observed in many solid tumors. The formation and metastases of tumors such as non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) are very complex, often regulated by proangiogenic factors such as the vascular endothelial growth factor (VEGF) and other tyrosine kinases. The VEGFR, EGFR and mTOR pathways have played critical roles in controlling cell proliferation and a Read More