Data generated by the investigators in this program project grant and others indicate that gamma-secretase inhibitors (GSIs) may be useful drugs in such diverse settings Alzheimer's Disease (AD), cancer, multiple sclerosis, and immune rejection, and that the adverse effects caused by GSIs are not insurmountable. We will use GSIs as tools to explore the therapeutic potential of targeting gamma-secretase in vivo. In the context of this program project the main goal of the chemistry core will be to synthesize sufficient GSI to support the studies in Projects 1-3 and develop methods to measure GSI levels in body fluids and tissues following in vivo dosing.
The aims of the Chemistry Core are:
Aim 1. To synthesize all four L-alanine-containing enatiomerically pure diastereomers of LY-411,575, an extremely potent gamma-secretase inhibitor (GSI), and to isolate large quantities of the most potent diastereomer of LY-411,575 for in vivo studies.
Aim 2. To develop a reliable method of qualitative and quantitative analysis of LY-411,575 stereoisomers and related analytes and metabolites in biological fluids and tissues.
Aim 3. To synthesize other GSIs required for the studies proposed in projects 1-3.
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