Even though the association of ?-amyloid peptide (A?) deposition and Alzheimer's Disease (AD) underpins the major hypothesis for disease progression and possibly causation and several drugs addressing the formation or removal of ?-amyloid plaques have entered clinical trials, no effective therapy exists to date for AD. This reality calls for new targets that are not based on ?-amyloid supply side or removal but address its toxic effects on critical neuronal survival, metabolic and plasticity pathways. There is widening recognition that AD is an insulin resistant state affecting the brain, a so-called 'type II diabetes'In our studies, we have found a potential novel therapy to both restore insulin sensitivity and hasten A? removal. We found literature precedence for an unnamed allosteric activator of the kinase PDK-1 (CAS 1180676-32-7 or PS48), a chlorophenyl pentenoic acid. When tested in cultured cells and cell-free systems, PS48 was found to be reverse the negative amyloid effect by restoring Akt activation. We propose to use its structure and activity as a scaffold for the discovery of additional like-acting compounds. In this way several small libraries based on PS48 will be prepared and tested to try and optimize the therapeutic effect and other pharmacologic properties of this lead compound.
The goal of this Phase I proposal is to develop lead pre-clinical compounds which restore normal insulin pathway function in individuals with sporadic Alzheimer's Disease (AD). There is significant evidence for dysregulation of the insulin pathway in AD. In our studies, we have found a potential novel therapy to restore insulin sensitivity and hasten A? removal.