Medicinal Chemistry

吸烟是发达国家可预防的死亡和疾病的最大原因之一。 与烟草有关的疾病造成约44万人死亡， 每年在美国的费用。发现有效治疗烟草成瘾的药物有 充其量只是适度有效，并伴有许多副作用。此外， 复发是成功治疗尼古丁依赖的最大障碍。因此，在本发明中， 开发治疗方法，可以减少复发的脆弱性，从而促进长期 戒烟是有效治疗尼古丁成瘾的关键。 项目1的目标是一个迭代的药物化学计划，旨在发现和优化新的 用于尼古丁治疗的有效和选择性食欲素-1（0X 1）受体拮抗剂的种类 成瘾将导出引导构效关系（SAR）的先导化合物的信息 从一组基于细胞的测定中，设计用于“功能性”表征化合物以供进一步使用， 在尼古丁成瘾的体内动物模型中进行测试，如项目2和3中所述。最好的化合物将 在项目4中描述的体外药物代谢试验中进行分析，以优先考虑体内使用的化合物。 我们提出了一些潜在的出发点，开发0X 1受体拮抗剂。的 原始文献和专利文献提供了用于开始SAR的大量先导分子。此外，最近 MLPCN HTS筛选活动已完成，在两项试验中寻找食欲素-1拮抗剂 格式.来自该筛选的数据已经鉴定了几种新的和新颖的食欲素-1受体拮抗剂。最后， 化学信息学方法，包括结构相似性搜索和我们内部的虚拟筛选 TSRI（~ 750，000个小分子）和商业化合物的化学文件将有助于快速打击 扩张.

Cigarette smoking is one of the largest causes of preventable death and disease in developed countries. Tobacco-related disease is responsible for approximately 440,000 deaths and $160 billion in health-related costs in the United States annually. Medications found to be effective for treating tobacco addiction are modestly efficacious at best, and are accompanied by numerous side-effects. In addition, high rates of relapse are considered the greatest obstacle to successfully treating nicotine dependence. Thus, development of therapeutics that can decrease vulnerability to relapse and thereby facilitate long-term abstinence is crucial for the effective treatment of nicotine addiction. The goal of Project 1 is an iterative medicinal chemistry program designed to discover and optimize new classes of potent and selective orexin-1 (0X1) receptor antagonists for the therapeutic treatment of nicotine addiction. Information about lead compounds guiding structure-activity-relationships (SAR) will be derived from a panel of cell-based assays designed to "functionally" characterize compounds for further use and testing in in vivo animal models of nicotine addiction as described in Projects 2 and 3. Best compounds will be profiled in vitro drug metabolism assays as described in Project 4 to prioritize compounds for in vivo use. We propose a number of potential starting points from which to develop 0X1 receptor antagonists. The primary and patent literature provides a multitude of lead molecules for SAR to begin. Additionally, a recent MLPCN HTS screening campaign has been completed looking for orexin-1 antagonists in two assay formats. Data from this screen has identified several new and novel orexin-1 receptor antagonists. Lastly, cheminformatic approaches including structure similarity searching and virtual screening of our in-house chemical files of TSRI (~750,000 small molecules) and commercial compounds will facilitate rapid hit expansion.