Glycogen synthase kinase 3 (GSK-3) inhibitors:Proof of concept and therapeutic opportunities for the treatment of diabetes, Alzheimer's disease, stroke & bipolar disorder

Since the mid-1990s there has been a near exponential rise in the level of glycogen synthase kinase-3 (GSK-3) related research. Consequently the therapeutic potential of GSK-3 inhibitors has become a major area of pharmaceutical interest. The present report, produced by LeadDiscovery analysts under the editorial guidance of field-leader, Dr Hagit Eldar-Finkelman, offers a state of the art overview of GSK-3 and analyses the therapeutic role that inhibitors of this enzyme may play. The report concludes that there is particularly strong evidence to support the development of GSK-3 inhibitors as 1) antihyperglycemic, insulin sensitizing and insulinotropin agents for use in diabetics; 2) inhibitors of neuronal apoptosis and neurological decline in stroke patients; 3) blockers of the accumulation and toxicity of Aß/tau in Alzheimer's disease. In addition, the GSK-3 inhibitory activity of diverse mood stabilizers suggests that bipolar disorder represents a further indication for this therapeutic class. Having demonstrated significant proof of concept to support the development of GSK-3 inhibitors for each of these conditions we introduce each disease describing clinical characteristics, epidemiology and current treatment practices. We conclude that each condition is a common, serious and unmet disease. Furthermore each of the effects demonstrated for GSK-3 inhibitors represents a state of the art approach to these diseases. For example insulin sensitization is currently viewed as a relevant approach to diabetes; inhibition of apoptosis is seen as an emerging target for stroke; mood stabilizers offer the first-line approach to bipolar disorder; and targeting Aß/tau is generally considered to represent one of the next major advances in Alzheimer's disease therapeutics. Less clear is the therapeutic impact that GSK-3 inhibitors may have on myocardial infarction, however this application is analyzed.

Having established a role for GSK-3 inhibitors in the treatment of diabetes, stroke, Alzheimer's disease and bipolar disorder, the market value of each of these conditions was overviewed and found to total at least $10 billion/year world-wide. Considering the proof of concept for the development of GSK-3 inhibitors and the size of the market for such molecules, drug development databases were analyzed to identify GSK-3 inhibitors. Few specific molecules were identified although considerable patent and basic research activity is reported, suggesting that the field is emerging. Individual patents are listed in order to identify leaders in the field. Leading GSK-3 inhibitors are therefore currently facing minimal class-related competition and we therefore identified competition from other pharmacological classes. In particular we identified drugs in development or on the market, as well as development trends for the treatment of diabetes, stroke, Alzheimer's disease and bipolar disorder. Diabetes was found to be an area of pharmaceutical development that has rapidly expanded over the past 4 years, with much of this activity centering on the development of insulin sensitizers. Molecules in development or on the market are identified and characterized. Likewise companies involved in the development and in-licensing of such molecules are identified. The fields of Alzheimer's disease, apoptosis inhibitors and bipolar disorder were subjected to similar analyses. Hence it was found that, in general, Alzheimer's disease represents a stable area of pharmaceutical activity, although closer inspection reveals a dramatic and recent increase in candidates that target Aß. Likewise, development activity focusing on apoptosis inhibitors has increased considerably over the past 3 years. In contrast bipolar disease is receiving little attention with respect to research activity and current developments are related to the identification of new indications for existing molecules. We conclude that the current pharmaceutical environment offers an excellent opportunity for the development of GSK-3 inhibitors since competition is at an early stage or in the case of bipolar disease minimal.

In conclusion, there is convincing evidence to support the development of GSK-3 inhibitors for the treatment of diabetes, stroke, Alzheimer's disease and bipolar disorder. Each of these markets is large and unmet suggesting that the development of GSK-3 inhibitors holds excellent opportunities for the pharmaceutical industry. This report offers key information to research, business development and marketing personnel wishing to evaluate these opportunities.