Glucokinase Activators for Diabetes Therapy

Type 2 diabetes is characterized by elevated blood glucose levels resulting from a pancreatic b-cell secretory insufficiency combined with insulin resistance, most significantly manifested in skeletal muscle and liver (1). If untreated, diabetic complications develop that cause loss of vision, peripheral neuropathy, impaired kidney function, heart disease, and stroke. The disease has a polygenic basis because numerous genes (the latest count exceeding 20) participate in its pathogenesis, but modern lifestyle characterized by limited physical activity and excessive caloric intake are critical precipitating factors for the current epidemic of type 2 diabetes worldwide (2). It appears that available treatments, including attempts at lifestyle alterations and drug therapies including insulin, are insufficient to stem the tide. Therefore, new approaches, including the development of therapeutic agents with novel mechanisms of action, are needed. Selection of new drug targets to treat type 2 diabetes has to be guided primarily by consideration of established physiological chemistry of glucose homeostasis and of prevailing views about the pathophysiology of type 2 diabetes because the genetics of the disease that could serve as another guiding principle remain prohibitively perplexing. The glucosephosphorylating enzyme glucokinase (GK) was identified as an outstanding drug target for developing antidiabetic medicines because it has an exceptionally high impact on glucose homeostasis because of its glucose sensor role in pancreatic b-cells and as a rate-controlling enzyme for hepatic glucose clearance and glycogen synthesis, both processes that are impaired in type 2 diabetes (3). Milestones in the 45-year history of GK research are listed in Supplementary Table 1 (Supplementary References S1–S27). In the mid1990s, Hoffmann La-Roche scientists conducted a high-throughput screen in search of small molecules that could reverse the inhibition of GK by its regulatory protein (GKRP, see further discussion below) and identified a hit molecule that reversed GKRP inhibition by directly stimulating GK (4). Lead optimization efforts resulted in the discovery of several potent preclinically effective and apparently safe compounds and culminated in the development of piragliatin (for example, see structures in Supplementary Fig. 1), which was advanced through phase 2 trials but was then discontinued for undisclosed reasons. Since the first 2003 report in Science (4) on the discovery and preclinical effects of GK activators (GKAs),.100 patents for GKAs, several publications, and disclosure of early studies in type 2 diabetes have contributed significantly to the proof of principle and keen interest of pharmaceutical industry for this class of new antidiabetic agents (5–13). In the following contribution, the essential aspect of the role of GK in glucose homeostasis, of the biochemical pharmacology of GKA, and of the current status of GKA research and development and therapeutic application are discussed.