Discovery of potent and selective neuropeptide Y Y2 receptor antagonist probes

发现有效且选择性的神经肽 Y Y2 受体拮抗剂探针

基本信息

批准号：
8452717
负责人：
Michael Darin Cameron
金额：
$ 77.36万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-10 至 2015-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The overall and specific goal of this application is the identification of novel high affinity and selective functional antagonists of the neuropeptide Y Y2 receptor subtype. We aim to identify, design and synthesize novel, potent, and selective Y2R antagonists as tools for research on alcohol dependence with potential as clinically effective therapeutic agents. We aim to achieve this goal via medicinal chemistry design based on existing Y2R ligands that are available or have been obtained in our high throughput screening efforts. The disease target, alcohol addiction and dependence, represents an enormous health burden on society and for which currently available pharmacotherapies have insufficient efficacy. We propose Y2R antagonism as a mechanism to achieve the therapeutic objective. While no clinical validation exists for the mechanism, the hypothesis supported by preclinical data from multiple sources. A translational research team composed of medicinal chemists, computational chemists, cell biologists, pharmacologists, and physiologists with extensive drug discovery experience is prepared to execute a molecule development program centered on the design, synthesis and evaluation of agents for that can be used in alcohol dependence research based on their actions at the NPY Y2 receptor. Compounds will be developed in an iterative cycle of ligand evaluation and re-design. Medicinal chemistry efforts will focus on development of new and better compounds. The in vitro pharmacology of novel compounds will be assessed in multiple cell-based assays and will include NPY receptor counterscreens to routinely determine potency and selectivity at a very early stage. DMPK properties of leads will be determined both in vitro and in vivo throughout the process as well. Additional in vivo assessments of compound activity on alcohol dependence, including a validated test for efficacy assessment in reducing alcohol self-administration in rats, will be performed in the NIH/NIAAA laboratory of Dr. Markus Heilig. All other work will be performed at extramural sites. Unique aspects of our approach include an early reliance upon selectivity data, DMPK information, and early animal efficacy studies.

描述（由申请人提供）：本申请的总体和具体目标是鉴定神经肽Y Y2 受体亚型的新型高亲和力和选择性功能拮抗剂。我们的目标是识别、设计和合成新型、有效的、选择性的 Y2R 拮抗剂，作为研究酒精依赖的工具，并有可能成为临床有效的治疗剂。我们的目标是通过基于现有 Y2R 配体的药物化学设计来实现这一目标，这些配体是可用的或已在我们的高通量筛选工作中获得的。酒精成瘾和依赖这一疾病目标给社会带来了巨大的健康负担，而目前可用的药物疗法对此效果不足。我们提出 Y2R 拮抗作用作为实现治疗目标的机制。虽然该机制尚无临床验证，但该假设得到了多个来源的临床前数据的支持。由具有丰富药物发现经验的药物化学家、计算化学家、细胞生物学家、药理学家和生理学家组成的转化研究团队准备执行一项分子开发计划，重点是可用于治疗酒精依赖的药物的设计、合成和评估基于它们对 NPY Y2 受体的作用的研究。化合物将在配体评估和重新设计的迭代循环中开发。药物化学工作将集中于开发新的、更好的化合物。新化合物的体外药理学将通过多种基于细胞的测定进行评估，并将包括 NPY 受体反筛选，以在非常早期阶段常规确定效力和选择性。在整个过程中，还将在体外和体内测定先导化合物的 DMPK 特性。化合物对酒精依赖活性的其他体内评估，包括减少大鼠自我饮酒功效评估的验证测试，将在 Markus Heilig 博士的 NIH/NIAAA 实验室进行。所有其他工作将在校外地点进行。我们方法的独特之处包括早期依赖选择性数据、DMPK 信息和早期动物功效研究。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metabolism considerations for kinase inhibitors in cancer treatment.

DOI：
10.1517/17425255.2010.506873
发表时间：
2010-10
期刊：
Expert opinion on drug metabolism & toxicology
影响因子：
4.3
作者：
Duckett DR;Cameron MD
通讯作者：
Cameron MD

Synthesis and SAR of selective small molecule neuropeptide Y Y2 receptor antagonists.

选择性小分子神经肽Y Y2 受体拮抗剂的合成和SAR。

DOI：
10.1016/j.bmcl.2012.04.107
发表时间：
2012
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Mittapalli,GopiKumar;Vellucci,Danielle;Yang,Jun;Toussaint,Marion;Brothers,ShaunP;Wahlestedt,Claes;Roberts,Edward
通讯作者：
Roberts,Edward

Therapeutic potential of neuropeptide Y (NPY) receptor ligands.