| Abstrakt: |
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, -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- agonists. These agents increase insulin sensitivity through multiple mechanisms. Despite obstacles, this area of research holds promise for the identification of new therapies. 11-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. |
