CHEMISTRY CORE

化学核心

• 批准号: 7034747
• 负责人: Todd E Golde
• 金额: $ 12.04万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034747
• 关键词: alanine; analytical chemistry; antineoplastics; aspartic endopeptidases; bioassay; drug design /synthesis /production; immunopharmacology; method development; neuropharmacology; peptide chemical synthesis; pharmacokinetics; protease inhibitor; stereoisomer

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.

研究人员在该计划项目赠款中产生的数据和其他数据表明伽马分泌酶 在这种不同的环境中，抑制剂（GSI）可能是有用的药物 硬化症和免疫抑制作用，GSIS造成的不利影响并不是无法克服的。我们将 使用GSI作为探索靶向体内γ-分泌酶的治疗潜力的工具。在此上面 计划项目化学核心的主要目标是合成足够的GSI以支持 在项目1-3中进行研究，并开发了测量体液和组织中GSI水平的方法 体内给药。 化学核心的目的是： 目的1。合成所有四个含L-411,575的含L-丙氨酸的纯纯映体纯映异构体 极有效的γ-分泌酶抑制剂（GSI），并分离大量最有效的非对映异构体 LY-411,575用于体内研究。 目的2。开发一种可靠的定性和定量分析的方法-411,575立体异构体 以及生物液和组织中的相关分析物和代谢产物。 目的3。综合项目1-3中提出的研究所需的其他GSI。