PD2005: A CNS active DAT inhibitor for improving cognitive deficits in traumatic

PD2005：一种 CNS 活性 DAT 抑制剂，用于改善创伤性认知缺陷

基本信息

批准号：
8060050
负责人：
SOMASUNDAR PRASAD GABBITA
金额：
$ 26.33万
依托单位：
P2D, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-05 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8060050
关键词：
Adverse effects Affinity American Animal Model Animal Testing Animals Anti-Cholinergics Arousal Attention Attention deficit hyperactivity disorder Benztropine Binding Centers for Disease Control and Prevention (U.S.)Clinical Clinical Research Cognition Cognitive deficits Corpus striatum structure Data Dopamine Dose Drug usage Evidence based treatment Extracellular Space FDA approved Feasibility Studies Foundations Goals Histologic Human Impairment In Vitro Injury Intervention Lead Length of Stay Libraries Methylphenidate Modeling Monkeys Nootropic Agents Occupations Parents Patients Pharmaceutical Preparations Phase Productivity Property Rattus Ritalin Schedule Self Administration Self-Administered Severities Short-Term Memory Small Business Innovation Research Grant Testing Tissues Traumatic Brain Injury Water active comparator addiction analog behavior test clinical care controlled cortical impact cost dopamine transporter drug of abuse effective therapy executive function frontal lobe improved inhibitor/antagonist memory process neurobehavioral neurotransmission preclinical study preference processing speed psychostimulant reuptake sham surgery transport inhibitor uptake working group

项目摘要

DESCRIPTION (provided by applicant): The purpose of the present SBIR Phase 1 feasibility study is to assess the efficacy of our selective dopamine (DA) transport inhibitor PD2005 in improving cognitive deficits associated with traumatic brain injury (TBI). Executive function deficits like short term or working memory, processing speed, and attention are commonly prevalent in TBI patients. TBI-associated cognitive deficits cost the US economy about $ 60 BN due to losses in job productivity. The Neurotrauma Foundation Working Group recently established evidence- based treatment standards to treat neurobehavioral sequelae after TBI [40]. The Group recommended use of methylphenidate (Ritalin(R)), which promotes DA agonism by inhibiting DA transporter (DAT), to improve TBI-associated cognitive deficits. However, methylphenidate possesses substantial abuse and addiction potential and is subject to Schedule II controls. Thus, a need exists for DA cognitive enhancers without abuse potential. The applicant organization's lead compound PD2005 is a selective DAT inhibitor as lead compound, which enhances cognition but possesses no abuse potential. Our lead compound is a benztropine analog. The parent molecule benztropine is an FDA- approved selective high affinity DAT inhibitor in clinical use for over 30 years. Unfortunately, benztropine is a potent anticholinergic. Extensive lead optimization studies with our proprietary library of benztropine analogs led to PD2005 which demonstrated no anticholinergic properties. PD2005 demonstrated a 7- fold greater DAT inhibition in binding studies and 10- fold lower striatal [3H] DA reuptake compared to methylphenidate. The lead compound when administered peripherally significantly improved working memory and sustained attention in an animal model of attention deficit. Finally, PD2005 demonstrated no abuse potential as assessed by monkey and rat self-administration studies. Overall, the preliminary data suggest that our lead compound has a lack of abuse potential and can demonstrate robust efficacy in improving TBI-associated cognitive deficits. Our sole Specific Aim is: Specific Aim: Assess the effect of PD2005on Working Memory in a controlled cortical impact rat TBI model. PD2005's efficacy will compared with MPH and vehicle- treated controls across differing injury severity (sham, mild, moderate and severe TBI). Working Memory will be assessed employing the water T-maze Delayed Non-Match to Place task. PUBLIC HEALTH RELEVANCE: In the present application, we propose preclinical studies to assess whether our proprietary compound, PD2005 - a selective inhibitor of the dopamine transporter, is an effective treatment for improving cognitive deficits after traumatic brain injury (TBI). These preclinical studies will assess the efficacy of PD2005 on cognitive deficits following mild, moderate or severe TBI. Additionally, the effect of a positive control, methylphenidate - a FDA-approved drug used to treat cognitive deficits in TBI patients will be assessed.

描述（由申请人提供）：本 SBIR 1 期可行性研究的目的是评估我们的选择性多巴胺 (DA) 转运抑制剂 PD2005 在改善与创伤性脑损伤 (TBI) 相关的认知缺陷方面的功效。 TBI 患者普遍存在短期或工作记忆、处理速度和注意力等执行功能缺陷。由于工作生产力下降，与 TBI 相关的认知缺陷给美国经济造成了约 600 亿美元的损失。神经创伤基金会工作组最近制定了治疗 TBI 后神经行为后遗症的循证治疗标准 [40]。该小组建议使用哌醋甲酯（Ritalin(R)）来改善与 TBI 相关的认知缺陷，该药物通过抑制 DA 转运蛋白 (DAT) 来促进 DA 激动。然而，哌醋甲酯具有严重的滥用和成瘾潜力，并受到附表 II 的管制。因此，需要没有滥用潜力的 DA 认知增强剂。申请组织的先导化合物PD2005是一种选择性DAT抑制剂作为先导化合物，可增强认知但不具有滥用潜力。我们的先导化合物是苯托品类似物。母体分子苯托品是 FDA 批准的选择性高亲和力 DAT 抑制剂，已在临床使用超过 30 年。不幸的是，苯甲托品是一种有效的抗胆碱能药。使用我们专有的苯托品类似物库进行了广泛的先导化合物优化研究，最终产生了 PD2005，它没有表现出抗胆碱能特性。与哌醋甲酯相比，PD2005 在结合研究中表现出 7 倍的 DAT 抑制作用和 10 倍的纹状体 [3H] DA 再摄取作用。当外周给药时，先导化合物显着改善了注意力缺陷动物模型的工作记忆和持续注意力。最后，根据猴子和大鼠自我给药研究的评估，PD2005 没有表现出滥用潜力。总体而言，初步数据表明我们的先导化合物缺乏滥用潜力，并且可以在改善 TBI 相关认知缺陷方面表现出强大的功效。我们唯一的具体目标是：具体目标：在受控皮质冲击大鼠 TBI 模型中评估 PD2005 对工作记忆的影响。 PD2005 的功效将在不同损伤严重程度（假手术、轻度、中度和重度 TBI）下与 MPH 和载体治疗的对照进行比较。将使用水 T 迷宫延迟非匹配放置任务来评估工作记忆。公共健康相关性：在本申请中，我们提出临床前研究，以评估我们的专有化合物 PD2005（多巴胺转运蛋白的选择性抑制剂）是否是改善创伤性脑损伤（TBI）后认知缺陷的有效治疗方法。这些临床前研究将评估 PD2005 对轻度、中度或重度 TBI 后认知缺陷的疗效。此外，还将评估阳性对照哌醋甲酯（FDA 批准的用于治疗 TBI 患者认知缺陷的药物）的效果。