Development of a Selective Muscarinic Agonist for the Treatment of Schizophrenia

开发用于治疗精神分裂症的选择性毒蕈碱激动剂

基本信息

批准号：
7272231
负责人：
EDWARD J MCGUIRE
金额：
$ 44.68万
依托单位：
COGNITIVE PHARMACEUTICALS, LTD
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-11-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7272231
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Address Adenylate Cyclase Affinity Agonist Analytical Chemistry Animal Model Animals Antipsychotic Agents Apomorphine Attention Back Binding Biological Assay Blood - brain barrier anatomy Brain Canis familiaris Cell Line Cells Clinical Clinical Trials Cognition Cognitive Cognitive deficits Data Development Dopamine Agonists Dose Drug Industry Drug Interactions Drug Kinetics Evaluation Feedback Goals Impaired cognition Impairment In Vitro Investigation Investments Lead Link Liquid Chromatography Measures Membrane Memory Metabolism Methods Modeling Muscarinic Acetylcholine Receptor Muscarinic Agonists National Institute of Mental Health Patients Penetration Pharmaceutical Preparations Pharmacology Phase Phosphatidylinositols Pirenzepine Primates Property Psychotic Disorders Psychotropic Drugs Rattus Research Rodent Safety Sampling Schizophrenia Scopolamine Screening procedure Series Short-Term Memory Site-Directed Mutagenesis Small Business Funding Mechanisms Small Business Innovation Research Grant Standards of Weights and Measures Synthesis Chemistry Testing Thiadiazoles Toxicogenetics United States Food and Drug Administration analog analytical method base biological preparation cognitive function disability drug development in vivo molecular modeling novel pre-clinical prepulse inhibition programs receptor receptor binding research clinical testing scale up tandem mass spectrometry

项目摘要

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to develop selective muscarinic agonists for the treatment of psychosis and cognitive dysfunction associated with schizophrenia. Cognitive deficits, including impaired memory function, are strongly linked to the long- term disabilities found in patients with schizophrenia. Amelioration of cognitive deficits associated with schizophrenia represents an important clinical target for drug development that has not been addressed by the pharmaceutical industry. Previous studies definitively identified CDD-0304 as a lead compound for the treatment of schizophrenia. Continuation of analog synthesis efforts and the pharmacological evaluation of CDD 0304 derivatives are proposed in this application, with an emphasis on identifying a back-up compound. Compounds within the series with particular receptor selectivity, CNS penetration, and efficacy in animal models of schizophrenia and cognitive function will be evaluated. In addition, pharmacokinetic properties and the safety of CDD-0304 and related compounds will be assessed. Specific aims include: 1) Synthesis and pharmacological evaluation of novel muscarinic agonists, 2) In vivo CNS penetration, functional activity, and selectivity, 3) Scale-up and analytical chemistry and 4) Further determination of ADME and toxic properties of CDD- 0304 and analogs. These studies, with some additional investment, will complete the preclinical package necessary to file an IND application with the Food and Drug Administration for a novel muscarinic agonist with potential utility in the treatment of schizophrenia. The overall goal of the proposed research is to develop new compounds for the treatment of psychosis and cognitive dysfunction associated with schizophrenia. Cognitive deficits, including impaired memory function, are strongly linked to the long- term disabilities found in patients with schizophrenia. Treatment of cognitive deficits associated with schizophrenia represents an important clinical target for drug development that has not been addressed by the pharmaceutical industry. The studies outlined in the proposal will help provide the data necessary for advancing a compound to clinical testing.

描述（由申请人提供）：拟议研究的总体目标是开发选择性的毒蕈碱激动剂来治疗与精神分裂症相关的精神病和认知功能障碍。认知缺陷，包括记忆功能受损，与精神分裂症患者的长期残疾有密切的联系。与精神分裂症相关的认知缺陷的改善代表了制药行业尚未解决药物开发的重要临床目标。先前的研究明确地将CDD-0304鉴定为治疗精神分裂症的铅化合物。在本应用中提出了模拟合成工作和CDD 0304衍生物的药理评估的继续，重点是识别备用化合物。该系列中具有特定受体选择性，CNS穿透性以及精神分裂动物模型和认知功能的功效的化合物将得到评估。此外，将评估药代动力学特性以及CDD-0304和相关化合物的安全性。具体目的包括：1）新型毒蕈碱激动剂的合成和药理学评估，2）体内渗透，功能活性和选择性，3）规模上升和分析化学和4）进一步确定CDD-0304和Analogs的ADM和毒性性质。这些研究以及一些额外的投资将完成与食品药品监督管理局提出IND应用所需的临床前套餐，用于一种新型毒蕈碱激动剂，并在治疗精神分裂症治疗方面具有潜在的效用。拟议研究的总体目标是开发新化合物，用于治疗与精神分裂症相关的精神病和认知功能障碍。认知缺陷，包括记忆功能受损，与精神分裂症患者的长期残疾有密切的联系。与精神分裂症相关的认知缺陷的治疗是药物开发的重要临床靶标，药物尚未解决。该提案中概述的研究将有助于提供将化合物推进临床测试所需的数据。