Strategies for the design of hepatoselective glucokinase activators to treat type 2 diabetes.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) represents a rapidly expanding healthcare challenge. There is a significant need for novel therapies to help patients achieve and maintain glycemic control in order to avoid the long-term microvascular and macrovascular complications associated with the disease. Small molecule allosteric activators of the glucokinase enzyme, an important regulator of glucose homeostasis, have emerged as a potential new class of therapeutics. Glucokinase activators have been shown to effectively lower fasting and postprandial glucose in T2DM patients; however, hypoglycemia emerged as a potential risk limiting their therapeutic potential. To mitigate this risk, recent efforts have focused on the design of liver-specific activators that seek to normalize hepatic glucose uptake and production without potentiating glucose-stimulated insulin secretion. AREAS COVERED: The article reviews the various drug discovery strategies that have emerged for the development of candidates that selectively activate glucokinase in the liver. Literature from 2000 to 2012 is surveyed including scientific publications, patent applications, conferences and clinical trials. EXPERT OPINION: Liver selective agents have proven to be an effective strategy for mitigating the hypoglycemia risk that has been historically associated with this mechanism. The ultimate therapeutic potential of this approach will depend on the results of longer patient studies which are currently being conducted with several clinical candidates. The discovery of these liver-specific activators has highlighted several challenges in the design of tissue-selective therapeutics, which will need to be overcome in the future.