Development of Novel Agents for CNS-related Diseases

中枢神经系统相关疾病新药的开发

基本信息

批准号：
7712516
负责人：
Seth Y Ablordeppey
金额：
$ 33.29万
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：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7712516
关键词：
Adverse effects Adverse event Affinity Age American Animal Model Antidepressive Agents Antipsychotic Agents Binding Biological Availability Capital Cardiovascular Diseases Censuses Central Nervous System Agents Clinic Clinical Clozapine Data Development Disease Dopamine D2 Receptor Drug Kinetics Dyslipidemias Environment Generations Goals Grant Health Care Costs Hyperlipidemia Hypotension Impaired cognition Individual Laboratories Lead Legal patent Licensing Link Mental disorders Metabolic syndrome National Institute of Mental Health New Agents Non-Insulin-Dependent Diabetes Mellitus Obesity Pharmaceutical Preparations Pindolol Publishing Research Research Proposals Schizophrenia Scientist Seizures Selective Serotonin Reuptake Inhibitor Series Serotonin Symptoms Syndrome Therapeutic Time Translating Treatment Efficacy United States National Institutes of Health Weight Gain atypical antipsychotic base clinical efficacy depression design improved in vivo inhibitor/antagonist novel olanzapine preclinical study public health relevance receptor reuptake serotonin transporter

项目摘要

DESCRIPTION (provided by applicant): According to the National Institute of Mental Health (NIMH), an estimated 26.2% of Americans ages 18 and above suffer from a diagnosable mental disorder in a given year. This percentage translates to about 60 million people per year using 2004 census figures. The long term goal of this proposal is to develop new agents that have improved therapeutic profiles over the current antipsychotics and antidepressants in use. Atypical Antipsychotic Agents (AAAs) or Second Generation Antipsychotics (SGAs), typified by clozapine and olanzapine, have replaced typical antipsychotic agents (TAAs) as the drugs of choice for the treatment of schizophrenia due to their superior side effect profiles. However, AAAs have now been found to produce a new set of adverse events including weight gain, obesity, type II diabetes, seizures, hypotension, hyperlipidemia and cardiovascular disease (CVD). Several of these new side effects have been linked to specific receptors in the CNS or the periphery. Thus, the goal of this research proposal is three-fold: to move a new lead identified in our laboratories towards the clinic by validating its in vivo activities, to optimize another new lead (SYA038) with the potential to overcome the side effects associated with the current AAAs and to optimize a third new lead compound (SYA031) with the potential to overcome the initial delay associated with serotonin reuptake inhibitors (SSRIs) in the treatment of depression and to improve their therapeutic efficacy. The following specific aims are proposed to achieve the objectives of the proposal: i) To validate the in vivo efficacy of SYA 013 in animal models of schizophrenia and to conduct bioavailability and pharmacokinetic analyses, ii) To conduct SAR studies on a new lead compound, SYA038, discovered during the previous MBRS cycle in order to optimize its affinity to both D2 and 5HT1A receptors but exclude high affinity at receptors linked to the adverse events, iii) To expand our exclusive focus on antipsychotic agents to a focus on novel antidepressants using a newly identified agent SYA031 with specific binding affinity for the serotonin transporter (SERT) and 5HT1A as a lead. Drugs with a combined capacity to inhibit SERT and 5HT1A may represent a novel class of drugs for treating depression. Achieving the specific aims will also provide preliminary data and improve our research environment such that we would become more competitive to apply for non-SCORE R-series grants from the NIH NIMH by the end of the grant period. PUBLIC HEALTH RELEVANCE: According to the National Institute of Mental Health (NIMH), an estimated 26.2% of Americans ages 18 and above suffer from a diagnosable mental disorder in a given year. This percentage translates to about 60 million people per year using 2004 census figures. The long term goal of this proposal is to develop new agents that have improved therapeutic profiles over the current antipsychotics and antidepressants in use. Providing new drugs for Schizophrenia and depression will elevate adverse side-effects associated with the current drugs and reduce health care cost associated with this debilitating illness. Achieving the specific aims will also provide preliminary data and improve our research environment such that we would become more competitive to apply for non-SCORE R-series grants from the NIH NIMH by the end of the grant period.

描述（由申请人提供）：根据国家心理健康研究所（NIMH）的说法，估计在给定年份中患有可诊断性精神障碍的18岁及以上的美国人中有26.2％。使用2004年的人口普查数据，该百分比每年约为6000万人。该提案的长期目标是开发与当前抗精神病药和使用抗抑郁药的新药物的新药物。以氯氮平和奥氮平的代表的非典型抗精神病药（AAAS）或第二代抗精神病药（SGA）取代了典型的抗精神病药（TAAS），作为由于其出色的副作用概况而导致的精神分裂症治疗的药物。但是，现在发现AAA会产生一系列新的不良事件，包括体重增加，肥胖，II型糖尿病，癫痫发作，低血压，高脂血症和心血管疾病（CVD）。这些新的副作用中的几种与中枢神经系统或外围的特定受体有关。 Thus, the goal of this research proposal is three-fold: to move a new lead identified in our laboratories towards the clinic by validating its in vivo activities, to optimize another new lead (SYA038) with the potential to overcome the side effects associated with the current AAAs and to optimize a third new lead compound (SYA031) with the potential to overcome the initial delay associated with serotonin reuptake inhibitors (SSRIs) in the treatment of抑郁并提高其治疗功效。提出了以下具体目的来实现该提案的目标：i）在精神分裂症的动物模型中验证SYA 013的体内功效，并进行精神分裂症的动物模型，并进行生物可用性和药代动力学分析，ii）在SYA038中进行新的铅元素的新铅及其在井中的新铅元素，但在井中发现了SAR研究，以使其在秩序中发现，但在52中发现了d2 d2 d2 d2 d2 d2。在与不良事件相关的受体中，iii）将我们对抗精神病药的专注侧重于使用新鉴定的剂Sya031对新型抗抑郁药的关注，其特定结合亲和力对5-羟色胺转运蛋白（SERT）和5HT1A的领先。抑制SERT和5HT1A的综合能力的药物可能代表一种用于治疗抑郁症的新型药物。实现具体目标还将提供初步数据并改善我们的研究环境，以便我们在赠款期末之前将从NIH NIMH申请非级R系列赠款。公共卫生相关性：根据国家心理健康研究所（NIMH）的说法，估计有26.2％的18岁及以上的美国人在特定年份患有可诊断的精神障碍。使用2004年的人口普查数据，该百分比每年约为6000万人。该提案的长期目标是开发与当前抗精神病药和使用抗抑郁药的新药物的新药物。为精神分裂症和抑郁症提供新药物将提高与当前药物相关的不良副作用，并降低与这种使人衰弱的疾病相关的医疗保健成本。实现具体目标还将提供初步数据并改善我们的研究环境，以便我们在赠款期末之前将从NIH NIMH申请非级R系列赠款。