A New Approach for the Development of Novel Antipsychotic Drugs

开发新型抗精神病药物的新方法

基本信息

批准号：
8999079
负责人：
Seth Y Ablordeppey
金额：
$ 33.78万
依托单位：
FLORIDA AGRICULTURAL AND MECHANICAL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8999079
关键词：
Adult Adverse effects Adverse event Affect Affinity Age American Animal Model Antipsychotic Agents Apomorphine Binding Biological Availability Brain Diseases Characteristics Chronic Schizophrenia Clinic Collaborations DRD2 gene Development Disease Drug Kinetics Evaluation Failure Feeling suicidal Functional disorder Funding Agency GTP-Binding Proteins Goals Grant Health Care Costs Heart In Vitro Joints Lead Learning MK801 Metabolic National Institute of Mental Health Neurobehavioral Manifestations New Agents Outpatients Patients Permeability Pharmaceutical Preparations Pharmacotherapy Population Postdoctoral Fellow Procedures Process Property Psychotic Disorders Publishing Rattus Reflex action Reporting Research Resistance Schizophrenia Sedation procedure Signal Transduction Social Interaction Solubility Structure Symptoms Teacher Professional Development Testing Therapeutic Weight Gain Writing analog arrestin 2 base beta-arrestin design drug development improved in vivo interest meetings morris water maze novel novel strategies novel therapeutics pre-clinical public health relevance pyrimidine analog receptor research study response screening small molecule spatial memory statistics stereotypy

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a brain disorder that affects about 1% of the world's population and out of this number, up to a third of patients are treatment-resistant (TRS). In addition, schizophrenia is associated with suicidal ideation and 9-13% of patients eventually take their own lives. Even more troubling is the fact that 65 to 80 % of outpatients with chronic schizophrenia discontinue their antipsychotic medications, often because of a lack of efficacy or intolerable adverse effects. There is therefore an urgent need for new antipsychotics that promote compliance and ultimately treat the disease including the treatment resistant illness. The long-term goal of this proposal is to develop novel small molecules that promote β-arrestin-2 recruitment to D2R and simultaneously interact at other CNS receptors involved in the pathophysiology of schizophrenia as new treatment options for schizophrenia. In addition, selected compounds should also not interact appreciably with receptors associated with the known side effects of current drugs. We have identified two lead compounds with this profile, SYA16263 and SYA16268 and they will form the basis of drug development to accomplish this long-term goal. The specific aims proposed to accomplish this goal, include evaluation of SYA 16263, a newly identified preclinical candidate, in a battery of tests in animal models of psychosis and to demonstrate a lack of adverse events enabling us then to move this drug or the related analog toward the clinic. Because of its newly characterized functional profile, we also plan to conduct a structure functional selectivity relationship study on SYA 16263. Specific Aim 2 will optimize the binding affinity of SYA 23013 and SYA 29875 two newly discovered agents in our labs, to D2R, 5HT1AR and 5HT7R while minimizing interactions at 5HT2BR, 5HT2CR and H1R (Ki > 500 nM). The design strategy is to obtain high potency compounds that promote b-arrestin-2 recruitment to D2R and function as antagonists (Ki<10 nM) at 5HT1AR, 5HT2AR and 5HT7R. Specific Aim 3 involves performing in vitro ADME and in vivo pharmacological evaluations of at least 1 agent per year obtained in specific aims 1 and 2 that satisfy stated physicochemical characteristics, including Lipinski's rule of five (Ro5), permeability and metabolic stability. Finally, as a faculty development grant, we also propose a specific Aim 4 which involves orchestrating a Faculty Development Strategy that will lead to obtaining non-SCORE grants. The activities include re-establishing a vibrant collaboration with experts in the field and hiring research associates/technicians to help PI deliver on the proposal aims, to establish a compound screening lab in FAMU; to write and publish ≥2 articles per year and to write at least one proposal including an R21 or RO1 per year to non-SCORE funding agencies and ≥2 joint RO1 proposals with collaborators.

描述（由申请人提供）：精神分裂症是一种脑部疾病，影响了世界人口的约1％，并且在这个数字中，多达三分之一的患者对治疗（TRS）。此外，精神分裂症与自杀念头有关，9-13％的患者最终夺走了自己的生命。更大的麻烦是，慢性精神分裂症的门诊患者中有65％至80％停止其抗精神病药物，这通常是由于缺乏效率或无法忍受的不利影响。因此，迫切需要新的抗精神病药，以促进依从性并最终治疗疾病，包括抗治疗疾病。该提案的长期目标是开发新型的小分子，这些分子促进β-arrestin-2募集到D2R，并简单地在与精神分裂症病理生理学的其他CNS受体相互作用，作为精神分裂症的新治疗选择。此外，选定的化合物也不应与与当前药物的已知副作用相关的接收器相互作用。我们已经确定了两种铅化合物SYA16263和SYA16268，它们将构成药物开发的基础，以实现这一长期目标。提议实现这一目标的具体目的包括对精神病动物模型的一系列测试中的SYA 16263评估SYA 16263，并证明缺乏不良事件，使我们能够将这种药物或相关的模拟转移到临床上。由于其新特征的功能概况，我们还计划在SYA 16263上进行结构功能性关系研究。具体目的2将优化SYA 23013和SYA的结合亲密关系29875在我们的实验室中两个新发现的代理，与D2R，5HT1AR和5HT7R相互作用，同时在5ht1r和5htt2br，5htt2br，5htt2br，5htt2br，5htt2br和5htt br的相互作用。设计策略是获得高效力化合物，可在5HT1AR，5HT2AR和5HT7R上促进B-arrestin-2募集到D2R并充当拮抗剂（Ki <10 nm）。特定的目标3涉及在特定目标1和2中每年至少获得1个药物的体外ADME和体内药理学评估，其中满足了陈述的物理特征，包括Lipinski的五（RO5）规则，渗透率和代谢稳定性。最后，作为教师发展赠款，我们还提出了一个特定的目标4，该目标涉及策划一项将导致获得非分数赠款的教师发展策略。活动包括与该领域的专家重新建立充满活力的合作并招聘研究协会/技术人员帮助PI以该提案的目的交付，以在FAMU建立复合筛查实验室；每年撰写和发表≥2篇文章，并至少编写一份提案，包括每年对非评分资金机构的R21或RO1，以及与合作者≥2个联合RO1提案。