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

• 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
• 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

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）：目前SBIR一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在改善创伤性脑损伤（TBI）相关认知缺陷方面的疗效。执行功能缺陷，如短期或工作记忆、处理速度和注意力，在TBI患者中普遍存在。由于工作效率下降，脑外伤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建立了基于证据的治疗标准来治疗创伤性脑损伤后的神经行为后遗症。该小组推荐使用哌甲酯（利他林(R)），它通过抑制DA转运蛋白（DAT）促进DA激动作用，以改善tbi相关的认知缺陷。然而，哌醋甲酯具有严重的滥用和成瘾性，受附表二管制。因此，需要无滥用潜力的DA认知增强剂。申请单位的先导化合物PD2005是一种选择性的DAT抑制剂作为先导化合物，具有增强认知的作用，但无滥用潜力。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，在临床使用超过30年。不幸的是，苯托品是一种有效的抗胆碱能药。利用我们专有的苯托品类似物库进行了广泛的先导物优化研究，结果显示PD2005没有抗胆碱能特性。与哌醋甲酯相比，PD2005在结合研究中显示出7倍的DAT抑制作用和10倍的纹状体[3H] DA再摄取。在注意缺陷动物模型中，外周给药的先导化合物显著改善了工作记忆和持续注意力。最后，在猴子和大鼠的自我给药研究中，PD2005显示没有滥用的可能性。总的来说，初步数据表明，我们的先导化合物缺乏滥用的可能性，可以在改善脑外伤相关的认知缺陷方面显示出强大的功效。目的：评价pd2005对脑外伤模型大鼠工作记忆的影响。PD2005的疗效将在不同损伤严重程度（假性、轻度、中度和重度TBI）下与MPH和车辆处理的对照组进行比较。工作记忆将采用水t迷宫延迟非匹配到位置任务进行评估。