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，影响着世界上约 1% 的人口，其中高达三分之一的患者对治疗有抵抗力 (TRS)。此外，精神分裂症与自杀意念有关，9-13% 的患者有自杀意念。更令人不安的是，65% 至 80% 的慢性精神分裂症门诊患者通常会因为某种原因而停止服用抗精神病药物。因此，迫切需要新的抗精神病药物来促进依从性并最终治疗疾病，包括治疗耐药性疾病。该提案的长期目标是开发促进β-抑制素的新型小分子。 -2 募集到 D2R 并同时与参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，所选化合物也不应与相关受体发生明显相互作用。我们已经确定了目前药物的已知副作用，即 SYA16263 和 SYA16268，它们将构成药物开发的基础，以实现这一长期目标。为实现这一目标而提出的具体目标包括评估。 SYA 16263 是一种新确定的临床前候选药物，在精神病动物模型中进行了一系列测试，并证明没有不良事件，使我们能够将这种药物或相关类似物推向临床。除了其新表征的功能特征外，我们还计划对 SYA 16263 进行结构功能选择性关系研究。具体目标 2 将优化我们实验室新发现的两种药物 SYA 23013 和 SYA 29875 对 D2R、5HT1AR 和 5HT7R 的结合亲和力同时最大限度地减少 5HT2BR、5HT2CR 和 H1R 的相互作用 (Ki > 500 nM)。策略是获得高效化合物，促进 b-arrestin-2 招募至 D2R 并作为 5HT1AR、5HT2AR 和 5HT7R 的拮抗剂（Ki<10 nM）发挥作用。具体目标 3 涉及至少进行体外 ADME 和体内药理学评估。每年在特定目标 1 和 2 中获得 1 种药剂，满足规定的理化特性，包括利平斯基五法则 (Ro5)、渗透性和代谢最后，作为教师发展补助金，我们还提出了一个具体的目标 4，其中涉及精心策划教师发展战略，该战略将导致获得非 SCORE 补助金，这些活动包括与该领域的专家重新建立充满活力的合作和招聘。研究助理/技术人员帮助 PI 实现提案目标，在 FAMU 建立一个化合物筛选实验室，每年撰写和发表 ≥ 2 篇文章，并每年至少撰写一篇提案，包括 R21 或 RO1 以获得非 SCORE 资助机构和 ≥2 份与合作者的联合 RO1 提案。