SPIGELMAN (UCLA) - MCSP- EXPLORATORY CHEMISTRY (EC)

这项研究是NIH帮助结束成瘾长期(Hear)倡议的一部分，该倡议旨在加快科学解决方案，以了解疼痛的基础并加强临床疼痛管理。 国家神经疾病和中风研究所和国家卫生研究院蓝图神经治疗网络http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm需要药物化学支持计划提供全方位的服务设施和工作人员，他们将支持从探索化学阶段开始的药物化学发现计划，以开发结构活性关系(SAR)分析和设计、合成、体外吸收、分布、代谢、排泄和毒理学(ADMET)，计算化学/计算机辅助药物发现(CADD)和化合物储存和运输物流，以支持Contributor Spigelman(UCLA)开发一种新的治疗口腔癌疼痛的有效方法。这将通过提高他们的小分子杂环起始化合物的SAR/SPR来实现，利用他们的检测和体外ADMET来确定针对物质使用障碍的目标酶的新型选择性抑制剂。我们的药物发现方法将是合成基于杂环支架的新型配体，这些都是有效的抑制剂。候选分子将接受分析，以评估与治疗环境中化合物的物理化学性质具体相关的标准，包括酶选择性和确定与关键代谢酶系统的潜在相互作用的测试。目标是推进项目进行/不进行的决策，并连续进行到每个选项阶段(开始命中到领导和开始领导优化)。本合同产生的数据将由NINDS、贡献者或受赞助的研究人员使用，以支持针对临床前活动的研究新药(IND)申请。该合同的努力结果将成为推进临床前候选化合物进一步开发的基础，即在准备IND文件时进行先进的PK和毒理学评估。

This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to understand the basis of pain and enhance clinical pain management. The National Institute on Neurological Disorders and Stroke (NINDS) and the NIH Blueprint Neurotherapeutics Network (BPN) http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm have a need for the Medicinal Chemistry Support Program (MCSP) to provide a full-service facility and staff who would support a medicinal chemistry discovery program beginning at the Exploratory Chemistry phase to develop structure activity relationship (SAR) analysis and design, synthesis, in vitro absorption, distribution, metabolism, excretion and toxicology (ADMET), computational chemistry/Computer Aided Drug Discovery (CADD) and compound logistics of storage and shipping to support the Contributor Spigelman (UCLA) to develop a novel therapeutic effective in oral cancer pain. This will be achieved by advancing the SAR/SPR of their small molecule heterocyclic starting compound utilizing their assays and in vitro ADMET to identify novel, selective inhibitors of the target enzyme that are directed at substance use disorder. Our drug discovery approach will be to synthesize novel ligands based on the heterocyclic scaffold that are potent inhibitors. Candidate molecules will undergo profiling to assess criteria specifically related to the physicochemical properties of compounds in a therapeutic setting, including enzyme selectivity and tests to determine potential interactions with key metabolic enzyme systems. The goal is to advance the project to go/no go decisions and to progress to each of the Option phases in succession (start of Hit to Lead and start of Lead Optimization). The data generated from this contract will be used by NINDS, contributors or sponsored investigators in support of Investigational New Drug (IND) application directed preclinical activities. The results of the efforts of this contract will be the basis to advance preclinical candidate compounds for further development i.e., advanced PK and toxicological evaluation in preparation of IND filings.