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：
7910593
负责人：
Seth Y Ablordeppey
金额：
$ 30.58万
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/7910593
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 Depression 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 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）：根据美国国家心理健康研究所 (NIMH) 的数据，估计 18 岁及以上的美国人在某一年有 26.2% 患有可诊断的精神障碍。根据 2004 年人口普查数据，这一百分比相当于每年约 6000 万人。该提案的长期目标是开发新药，与目前使用的抗精神病药和抗抑郁药相比，改善治疗效果。以氯氮平和奥氮平为代表的非典型抗精神病药（AAA）或第二代抗精神病药（SGA）因其优越的副作用而取代了典型抗精神病药（TAA）成为治疗精神分裂症的首选药物。然而，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)。其中一些新的副作用与中枢神经系统或外周的特定受体有关。因此，这项研究计划的目标有三个：通过验证其体内活性，将我们实验室鉴定的新先导药物推向临床；优化另一种新先导药物（SYA038），该新先导药物有可能克服与药物相关的副作用。并优化第三种新的先导化合物（SYA031），该化合物有可能克服与血清素再摄取抑制剂（SSRI）治疗抑郁症相关的初始延迟并提高其治疗效果。为了实现该提案的目标，提出了以下具体目标：i) 验证 SYA 013 在精神分裂症动物模型中的体内功效，并进行生物利用度和药代动力学分析，ii) 对新的先导化合物进行 SAR 研究， SYA038是在之前的MBRS周期中发现的，目的是优化其对D2和5HT1A受体的亲和力，但排除与不良事件相关的受体的高亲和力， iii) 将我们对抗精神病药物的独家关注扩展到新型抗抑郁药物，使用新鉴定的对血清素转运蛋白 (SERT) 具有特异性结合亲和力的药物 SYA031 和 5HT1A 作为先导药物。具有抑制 SERT 和 5HT1A 联合能力的药物可能代表一类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，以便我们在资助期结束时更有竞争力地申请 NIH NIMH 的非 SCORE R 系列资助。公共健康相关性：根据美国国家心理健康研究所 (NIMH) 的数据，18 岁及以上的美国人在某一年估计有 26.2% 患有可诊断的精神障碍。根据 2004 年人口普查数据，这一百分比相当于每年约 6000 万人。该提案的长期目标是开发新药，与目前使用的抗精神病药和抗抑郁药相比，改善治疗效果。提供治疗精神分裂症和抑郁症的新药将增加与现有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费用。实现具体目标还将提供初步数据并改善我们的研究环境，以便我们在资助期结束时更有竞争力地申请 NIH NIMH 的非 SCORE R 系列资助。