Core--Medicinal chemistry: discovery and screening

核心--药物化学：发现与筛选

• 批准号: 7055205
• 负责人: JOHN S. LAZO
• 金额: $ 18.42万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7055205
• 关键词: biomedical facility; cooperative study; drug design /synthesis /production; drug screening /evaluation; radioprotective agents

Scavengers of reactive oxygen species (ROS) and mitochondria! nitric oxide synthase (mtNOS) inhibitors play a key role in the development of novel orally administrable radioprotectants and mitigators. The Core has two interdependent and integrated Sections: (a) Medicinal (Discovery) Chemistry, and (b) Pharmacological Evaluation and Formulation. The overall goal of the Medicinal (Discovery) Chemistry section of the Core is to provide novel, chemoreversible and thus timed-release agents. The overall goal of the Pharmacology Section of the Core is to provide resources to allow in vitro high throughput screening of chemical libraries, to provide an initial evaluation of the cellular activity of newly synthesized compounds, and to conduct formulation and stability studies for the CMCR Projects and Cores. We have five specific tasks: 1. Preparation of peptide mimetics based timed-release derivatives of ROS scavengers (TEMPO derivatives) and mtNOS inhibitors. These agents will be cell-permeable and membrane-targeted. 2. Synthesis of cell-permeable peptide antioxidants specifically targeted to the inner mitochondrial membrane. 3. Implementing automated high throughput screening assays. 4. Conducting multiparametric analyses of newly synthesized compounds in intact cells. 5. Formulating compounds for in vivo intravenous and oral use, evaluating chemical extraction methods to prepare the samples for analytical analysis, and determine compound stability in aqueous and biological fluids.

活性氧（ROS）和线粒体的清除剂！一氧化氮合酶（MTNOS）抑制剂在新型口服辐射保护剂和缓解剂的发展中起关键作用。核心有两个相互依存和综合的部分：（a）药物（发现）化学，以及（b）药理学评估和制定。核心的药用（发现）化学部分的总体目标是提供新颖的，化学性的，因此定时释放剂。核心的药理学部分的总体目标是提供资源以允许化学文库的体外高吞吐量筛查，以对新合成化合物的细胞活性进行初步评估，并对CMCR项目和核心进行制剂和稳定性研究。我们有五个特定的任务： 1。基于肽模拟物的制备ROS清除剂的定时释放衍生物（Tempo） 衍生物）和mTNOS抑制剂。这些药物将是可渗透和膜的细胞靶向。 2。特异性针对内部线粒体膜的可渗透肽抗氧化剂的合成。 3。实施自动高吞吐量筛选分析。 4。对完整细胞中新合成化合物进行多参数分析。 5。制定体内静脉内和口服的化合物，评估化学提取方法以制备样品进行分析分析，并确定水和生物流体中的复合稳定性。