Current Topics in Medicinal Chemistry - Volume 8, Issue 17, 2008

The International Diabetes Federation estimates that in 1985, 30 million people had diabetes. By 2000, this number had increased to 150 million. In 2025, 380 million people will be afflicted by this disease. Type 2 diabetes accounts for more than 85% of these cases. The reasons for this alarming growth are an aging population, unhealthy diets, lack of exercise and increasing obesity [1]. Diabetes is the fourth leading cause of death by disease and is associated with serious complications. Every 10 seconds a person dies from diabetes-related causes. People with diabetes are twice as likely to have a heart attack or a stroke. Diabetic retinopathy is the leading cause of vision loss in adults. Diabetes is the leading cause of kidney failure. Most nontraumatic lower-limb amputations are a result of diabetic neuropathy [1, 2]. Type 2 diabetes is characterized by reduced insulin sensitivity, β-cell dysfunction and inappropriate hepatic glucose production. Pharmacological interventions focus on one or more of these defects. In this issue, the medicinal chemistry approaches applied to several current and emerging treatment paradigms will be reviewed. In the first article, Nobuo Cho and Yu Momose (Takeda Pharmaceutical Company Limited) review PPAR-γ agonists. These agents increase insulin sensitivity through multiple mechanisms. Despite obstacles, this area of research holds promise for the identification of new therapies. 11β-HSD1 inhibitors have the potential to treat both diabetes and obesity by limiting activation of the glucocorticoid receptor. Although clinical results have not been published, some of these agents have progressed as far as phase II. This area is reviewed by David St. Jean, Jr., Minghan Wang and Christopher Fotsch of Amgen. In the next article, Joseph Grimsby, Steven J. Berthel and Ramakanth Sarabu (Roche) give an overview of Glucokinase activators, which work in the pancreas to increase insulin production and in the liver to reduce glucose production. A successful drug in this target class should provide powerful blood glucose lowering. Several GK activators are now in clinical trials. Activation of SIRT1 improves insulin sensitivity and lowers plasma glucose in rodent models of diabetes. Moreover, as outlined by Bruce G. Szczepankiewicz and Pui Y. Ng (Sirtris), SIRT1 activators have the potential to treat numerous diseases associated with aging, including neurodegenerative diseases and cancer. In the final article, I review the medicinal chemistry approaches that were applied in five DPP-4 inhibitor discovery programs. These agents preserve endogenous GLP-1 leading to potentiation of glucose-stimulated insulin release and reduction in glucagon secretion. The targets covered in this issue represent only a fraction of the targets being pursued for the treatment of diabetes. Notable omissions from this compilation include SGLT-2, GPR40, glucagon receptor, FBPase and others. Perhaps these can provide the basis for another issue. I hope you enjoy this issue and learn from the other authors as much as I have. I would like to thank Dr. Edcon Chang, Dr. Andrew Jennings and Dr. Jeffrey A. Stafford for critical reading of some of these reviews.

An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. The peroxisome proliferatoractivated receptor γ (PPARγ) is one of the ligand-activated transcription factors in the nuclear hormone receptor superfamily and a pivotal regulator of glucose and lipid homeostasis. The discovery of PPARγ as a target of multimodal insulin sensitizers, represented by thiazolidinediones (TZDs), has attracted remarkable scientific interest and had a great impact on the pharmaceutical industry. With the clinical success of the PPARγ agonists, pioglitazone (Actos) and rosiglitazone (Avandia), development of novel and potent insulin-sensitizing agents with diverse clinical profiles has been accelerated. Currently, a number of PPARγ agonists from different chemical classes and with varying pharmacological profiles are being developed. Despite quite a few obstacles to the development of PPAR-related drugs, PPARγ-targeted agents still hold promise. There are new concepts and encouraging evidence emerging that suggest this class can yield improved anti-diabetic agents. This review covers the discovery of TZDs, provides an overview of PPARγ including the significance of PPARγ as a drug target, describes the current status of a wide variety of novel PPARγ ligands including PPAR dual and pan agonists and selective PPARγ modulators (SPPARγMs), and highlights new approaches for identifying agents targeting PPARγ in the treatment of type 2 diabetes.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests that selective inhibition of 11β-HSD1 could potentially treat the metabolic syndrome. This review provides an overview of compounds reported to have in vivo inhibitory activity against this enzyme. A major focus of this review is Amgen's 11β-HSD1 program which includes a variety of in vivo data for a lead compound from our thiazolone class of inhibitors. Finally, an update on the current known clinical data is discussed.

The search for innovative and clinically-differentiated medicines for the treatment of type 2 diabetes is an active area of research for pharmaceutical companies. The discovery of allosteric Glucokinase (GK) activators in 2003 represents the first time a pharmaceutical agent was used to directly augment the actions of an enzyme by increasing its maximal velocity and substrate affinity. This discovery, coupled with translational medicine which has shown that inactivating and activating GK mutations cause glycemic diseases, has triggered an intensive medicinal chemistry effort in the field of glucokinase activators (GKAs). The antidiabetic effects of GK activators observed in animal models support the notion that these agents act to both augment insulin release from pancreatic β-cells and suppress hepatic glucose production in the liver. This review describes the unprecedented task of optimizing small molecules in order to affect the appropriate changes in the kinetic parameters of an enzyme. In addition, a pharmacophore model for the various classes of glucokinase activators that have been described in the literature will be presented. Overall, the available data suggests that potent glucokinase activators with the desired effects on the kinetic properties of the enzyme can be designed to achieve strong and persistent antidiabetic effects. GK activators thus represent a promising new treatment for type 2 diabetes.

Over the past ten years, sirtuins have emerged as an important class of drug targets. These enzymes play an important role in gene activation and silencing in all organisms from prokaryotes to humans. There is evidence that sirtuin modulation can be beneficial for a wide variety of diseases associated with aging. Among these conditions are diabetes, neurodegenerative diseases, and cancer. Agents that activate some sirtuins may be beneficial, while inhibitors of other sirtuins might represent treatment options. This review covers the chemical activators and inhibitors of the sirtuins that have appeared in the literature through the first half of 2008.

Inhibitors of dipeptidyl peptidase IV (DPP-4) have emerged as an important new class of therapeutic agents for type two diabetes. Various medicinal chemistry approaches have been applied to this area and have resulted in the identification of numerous late-stage development compounds. The discoveries of several of the most advanced DPP-4 inhibitors are reviewed.

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