CHEMISTRY CORE

这个项目的研究人员格兰特和其他人产生的数据表明，伽马分泌酶 抑制剂(GSI)在阿尔茨海默病(AD)、癌症、多发性硬化等不同环境中可能是有用的药物 他们认为，GSIs引起的不良反应并不是无法克服的。我们会 在此背景下 方案项目化学核心的主要目标将是合成足够的GSI来支持 项目1-3中的研究，并开发方法来测量体液和组织中的GSI水平 活体剂量。 化学核心的目标是： 目的1.合成LY-411,575和LY-411,575的四个含L丙氨酸对映异构体。 非常有效的伽马分泌酶抑制剂(GSI)，并分离出大量的最有效的非对映异构体 LY-411,575用于体内研究。 目的：建立可靠的LY-411,575立体异构体的定性和定量分析方法 以及生物液和组织中的相关分析物和代谢物。

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.