Current Topics in Medicinal Chemistry - Volume 10, Issue 4, 2010

Obesity is an extremely common negative physical condition which has an increasing incidence in developed and some developing countries. It means that the accumulation of excessive body fat has become a threat to one 's health. Obesity is dangerous for it is closely associated with a number of terrible diseases, primarily known as type 2 diabetes, bilary, cardiovascular diseases and metabolic syndrome. According to statistics published in 2007 by The Centers for Disease Control and Prevention, 34% of U.S. adults ages 20 and over are suffering from obesity. With the rapidly growing health-care expenditure spent on obesity related diseases, it has become an urgent social problem. Typical primary treatments of obesity are reducing caloric in-take and increasing physical exercise. Drug therapy is required if this fails to achieve the desired results. In some severe cases, surgery is needed. To date, only two anti-obesity drugs have been approved by the FDA for long-term use, both of which have a list of obvious side-effects. Some other important candidates, i.e. Acomplia, have been canceled mainly for safety considerations. Hence, new therapy targets and screening strategies become the hot, new focus of research for novel anti-obesity drugs with desirable pharmacological profiles and fewer side-effects. This issue of Current Topics in Medicinal Chemistry, dedicated to “The Medicinal Chemistry of New Agents to Treat Diabetes and Obesity,” is aimed at describing and highlighting the state of the art of current research and development in the field of diabetes and obesity. The purpose of our current issue is to address the action mechanisms and applications of important anti-obesity targets. Natural products with anti-diabetic activity are also briefly reviewed. This issue presents reviews from five research groups which are involved in the investigation of anti-obesity agents. Min Zhong starts this issue with a review of the biological rationale of TGR5 as an attractive therapeutic target and summarizes the recent efforts in developing promising TGR5 modulators. TGR5 is a membrane G-protein-coupled protein receptor (GPCR) that responds to bile acids, and its modulators may contribute to the prevention and/or the treatment of obesity, type 2 diabetes and metabolic syndrome. It would be promising to see some preclinical and/or clinical results of potent and selective TGR5 modulators in the future. The second review by Li-Fang Yu et al. focuses on AMP-activated protein kinase (AMPK) and the potency of its direct or indirect activators which lead to a series of positive physical effects to improve metabolic diseases including obesity and type 2 diabetes. Many agents have been identified as direct or indirect activators of AMPK, including biguanides and thiazolidinediones. The major challenge of utilizing AMPK activators as novel agents for the treatment of obesity or type 2 diabetes is avoiding the risk of heart disease or the activation effect in the hypothalamus while keeping the original pharmacological effects.

TGR5 (also known as GPBAR1, M-BAR, BG37, hGPCR19, and AXOR 109) is a specific membrane Gprotein- coupled receptor (GPCR) of bile acids (BAs). It has recently become an attractive therapeutic target for the prevention and/or the treatment of obesity and its highly associated Type II diabetes and metabolic syndrome. It has also been implicated in many other inflammatory, cardiovascular, neurological, and hepatic diseases. This review briefly describes the biological rationale of TGR5 as an attractive therapeutic target and summarizes some recent efforts on the development of TGR5 modulators.

AMPK is a potential target of metabolic diseases including obesity and type 2 diabetes. The activation of AMPK can lead to an increase of glucose uptake into muscle, decreased gluconeogenesis in liver, increased fatty acid oxidation in muscle and liver, decreased fatty acid synthesis in liver and adipose tissue, and increase mitochondrial biogenesis. Until now, many efforts from industrial and academia have been focused on searching novel agents that activate AMPK directly or indirectly. This review will discuss recent advances in the search for novel therapeutic agents that mediate their activity via AMPK activation.

Plasma glucose is continuously filtered through the glomerulus and then is reabsorbed via the transcellular transport system of proximal tubules in the kidney. The glucose reabsorption system in the kidney is mediated by sodiumdependent glucose cotransporters (SGLTs). Most of filtered glucose is reabsorbed by the low affinity, high capacity SGLT2 located in the proximal renal tubule. SGLT2 inhibitors, such as T-1095, enhance urinary glucose excretion and consequently lower blood glucose levels independent of insulin action. The principle behind SGLT inhibition involves the amelioration of diabetic conditions without increasing body weight and the risk of hypoglycemia. A number of SGLT2 inhibitors are being developed for the treatment of diabetes. This review offers the summary of structure-activity relationships (SARs) and pharmacological profiles of T-1095 and diverse SGLT2 inhibitors.

SCD1 is a novel target for the treatment of dyslipidemia, obesity, and other symptoms of metabolic syndrome. Extensive target validation has been obtained using SCD1-deficient mice, anti-sense oligonucleotide and RNA interference-mediated knockdown of SCD1, and has supported a controlling role for SCD1 in regulation of lipid biosynthesis and energy expenditure. In this review, the recent advances in small-molecule SCD1 inhibitors will be summarized. The pharmacological and adverse effects of SCD1 inhibitors in relevant rodent models will also be reviewed. The future prospect of SCD1 inhibition in the treatment of metabolic diseases will be discussed.

Diabetes mellitus (DM), the third killer of the mankind health along with cancer, cardiovascular and cerebrovascular diseases, is one of the most challenging diseases facing health care professionals today. The World Health Organization (WHO) has declared that a DM epidemic is underway. Primary DM and its complications are costly to manage, not only for affected individuals, but also for healthcare systems around the world. Screening of anti-diabetic agents has been extensively investigated in the past decades. Natural products (NPs) have served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural substances. Many natural products especially plants-derived medicines have been recommended for the treatment of DM. The present paper reviews NPs appeared in the literature with potential for DM and also identifies the research needs in this area. It mainly covers the time period from January 2004 to June 2009. The current review is divided into three major sections based on classification of the natural materials involved. The first part focuses on known and some new chemical entities isolated mainly from medicinal plants possessing anti-diabetic properties, including saponins, flavonoids, alkaloids, anthraquinones, terpenes, coumarins, phenolics, polysaccharides, and some other compounds. The second part summarizes crude extract of medicinal plants which are commonly used in the traditional Chinese medical system and have been demonstrated experimental or/and clinical anti-diabetic effectiveness, mainly including Leguminosae, Cucurbitaceae, Araliaceae, Liliaceae, Chenopodiaceae, Solanaceae, Compositae, Campanulaceae, Cornaceae, Rhamnaceae, Scrophulariaceae, Euphorbiaceae, Ginkgoceae, Gramineae, Myrtaceae, Sterculiaceae, Annonaceae, Labiatae, Crassulaceae, and Miscellaneous. The third part lists some compound formulae consisting of extracts of several plants that have been reported as beneficial for the treatment of DM, major involving Xiaokeling tablet, Huang-Lian-Jie-Du-Decoction, Ba- Wei-Di-Huang-Wan and Formula 1.

This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB) as a reprise of our 2005 review with new data from the 2006-2009 time period. Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for cancer therapy and inhibition of Akt alone or in combination with standard cancer chemotherapeutics has been postulated to reduce the apoptotic threshold and preferentially kill cancer cells. Recently, several series of small molecule, ATP-competitive inhibitors have been reported with a range of Akt potencies and selectivities. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other pleckstrin homology (PH) domain containing proteins and may have poor bioavailability. In addition, novel allosteric inhibitors have been reported which are PH domain dependent, exhibit selectivity for the individual Akt isozymes and inhibit the activity and the activation of Akt. Compounds within these classes Akt inhibitors have sufficient potency and specificity which have culminated in recent reports of efficacy in tumor xenograft models. Moreover, Merck just disclosed positive Phase I data with an oral allosteric Akt inhibitor (MK-2206).