CHEMISTRY CORE

研究人员在该项目中获得的数据表明，γ-分泌酶 抑制剂（GSI）可能是用于阿尔茨海默病（AD）、癌症、多发性硬化症（MDS）、糖尿病（DM）、糖尿病性痴呆（AD）、糖尿病性痴呆（DM）等多种疾病的药物。 硬化和免疫排斥，并且由GSI引起的不利影响并非不可克服。我们将 使用GSI作为工具，探索体内靶向γ-分泌酶的治疗潜力。结合这一 化学核心的主要目标将是合成足够的GSI，以支持 项目1-3中的研究，并制定方法来测量体液和组织中的GSI水平， 体内给药。 化学核心的目标是： 目标1。为了合成LY-411，575的所有四种含L-丙氨酸的对映异构体纯的非对映异构体， 非常有效的γ-分泌酶抑制剂（GSI），并分离出大量的最有效的非对映体 LY-411，575用于体内研究。 目标2.建立LY-411，575立体异构体的定性定量分析方法 以及生物体液和组织中的相关分析物和代谢物。 目标3：综合项目1-3中提议的研究所需的其他全球统计信息。

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.