There is a growing consensus that the pivotal event in the pathophysiology of Alzheimer's disease (AD) is overproduction of amyloid beta peptide (Abeta). If this formulation is correct, then there are three primary strategies for interrupting the pathologic cascade: inhibiting beta-secretase, inhibiting gamma-secretase, or augmenting alpha-secretase. Intuitively, if Abeta is the culprit, reducing the generation of the peptide is the most promising approach. Both beta- and gamma-secretase are necessary for generation of intact Abeta, while alpha-secretase cleaves within the Abeta domain, preventing its release intact. The pharmaceutical industry has invested heavily in the development of beta- and gamma-secretase inhibitors, though none has yet succeeded in human trials. We propose a strategy based on the third approach, augmenting alpha-secretase activity. Our approach to augmenting alpha-secretase activity involves modulating protein kinase C (PKC), which has conclusively been linked to regulation of alpha-secretase in a number of laboratories. In this regard, we have shown recently that the structurally novel PKC activator, 8-(1-decynyl)-benzolactam, is able to reverse K+ channels defects and to enhance the production of the alpha-secretase product sAPPalpha in AD cells. More importantly, when tested in vivo, this benzolactam significantly increased the amount of sAPPalpha and reduced Abeta40 in the brains of APP[V7171] transgenic mice. Given the promising animal data achieved with the 8-(1-decynyl)-benzolactam and our long experience in the SAR of the benzolactams (BL), we propose to conduct a highly focused study aimed at defining the best benzolactam analog that can serve as a clinical candidate for the treatment of AD. To achieve this goal, our aims become the following: 1. Conduct both compound design using molecular modeling tools and the chemical synthesis of novel BLs with the aim to optimize effects on alpha-secretase activity while diminishing any possible tumor promoting activity; Much of this work will focus on altering the nature of the side chain appendages; 2. Carry out in vitro studies to define the biological activity of new analogs. Screen all compounds for activity as PKC activators. Test selected potent PKC activators (EC50 at least 50 nM) on levels of sAPPalpha and Abeta 1-40 and 1-42. Test compounds effective in enhancing sAPPalpha production for tumor promoting effects; 3. For the best compounds from Aim 2, perform studies in triple transgenic mice to ascertain effects on Abeta and sAPPalpha levels and plaque formation in vivo.
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