ADHD Therapeutic: PD2005 DA Transport Inhibitor

摘要 SBIR 1期临床前研究证明了我们的专利化合物PD 2005的疗效， 治疗注意力缺陷多动障碍（ADHD）。PD 2005是一种选择性多巴胺（DA） P2 D正在开发用于治疗ADHD的转运抑制剂。的美国学院 儿科确定非选择性DA转运抑制剂哌甲酯和安非他明为 只有被批准的ADHD一线治疗药物这些一线治疗药物是附表二滥用药物 主要用于儿童。相比之下，PD 2005在研究中未显示出滥用可能性 国家药物滥用研究所（NIDA）。拟议研究的长期目标是 开发一种安全有效的ADHD治疗方法，具有有限的滥用潜力（非计划或计划 IV）。 PD 2005是苯托品类似物。Benztropine是一种高亲和力DA转运抑制剂， 并被FDA认可有效，临床使用超过30年。苯扎托品显示无显著性 有滥用的可能，是一种非附表药物。不幸的是苯托品在临床上有显著的抗- 胆碱能副作用排除了其作为ADHD治疗的用途。广泛的潜在客户优化研究 已经用我们专有的苯托品类似物库进行了测试。初步研究表明 我们的先导化合物PD 2005没有表现出抗胆碱能的副作用，包括抗 苯扎托品特有的胆碱能心血管副作用（心动过速）。此外，PD 2005 安全性和毒理学研究由美国食品和药物管理局委托进行， (FDA)药物评价中心（CDER）。无PD 2005致癌性、致畸性、致突变性或 在这些FDA计算研究中发现了主要器官系统的毒理学。这些数据突出 PD 2005的安全性改善 SBIR 1期研究表明，PD 2005与目前的一线ADHD一样有效 治疗。首先，PD 2005在改善工作记忆方面与一线ADHD治疗一样有效， 核心ADHD症状，在一个公认的临床前ADHD模型。第二，PD 2005与 在另一个研究中， 公认的临床前ADHD模型。其他初步研究表明PD 2005是有效的 口服后。 拟议研究是FDA要求提交的安全性和毒理学研究， PD 2005研究性新药（IND）申请，允许在以下情况下将PD 2005用于人体： 参阅会议过程所有拟议的研究都将汇编在研究报告中，提交给FDA并进行讨论 与FDA进行面对面的IND前会议，以评估PD 2005是否符合FDA ICH M3 IND 指南

ABSTRACT SBIR Phase 1 preclinical studies demonstrate the efficacy of our proprietary compound, PD2005, for treating Attention Deficit/Hyperactivity Disorder (ADHD). PD2005 is a selective dopamine (DA) transport inhibitor that P2D is developing for the treatment of ADHD. The American Academy of Pediatrics identifies the non-selective DA transport inhibitors methylphenidate and amphetamine as the only approved first-line treatments for ADHD. These first-line treatments are Schedule II drugs of abuse administered primarily to children. In contrast, PD2005 demonstrates no abuse potential in studies conducted at the National Institute on Drug Abuse (NIDA). The long term goal of the proposed studies is to develop a safe and effective ADHD treatment with limited abuse potential (non-Scheduled or Schedule IV). PD2005 is a benztropine analog. Benztropine is a high affinity DA transport inhibitor found safe and effective by the FDA and in clinical use for over 30 years. Benztropine demonstrates no significant abuse potential and is a non-Scheduled drug. Unfortunately, benztropine's clinically significant anti- cholinergic side effects preclude its use as an ADHD treatment. Extensive lead optimization studies have been performed with our proprietary library of benztropine analogs. Preliminary studies indicate that our lead compound, PD2005, demonstrates no anti-cholinergic side effects including the anti- cholinergic cardiovascular side effect (tachycardia) characteristic of benztropine. Additionally, a PD2005 safety and toxicology study was commissioned and performed by the US Food and Drug Administration's (FDA) Center for Drug Evaluation (CDER). No PD2005 carcinogenicity, teratogenicity, mutagenicity or toxicology in major organ systems was found in these FDA computational studies. These data highlight the improved safety profile of PD2005 SBIR Phase 1 studies demonstrate that PD2005 is as effective as current first-line ADHD treatments. First, PD2005 is as effective as first-line ADHD treatments at improving working memory, a core ADHD symptom, in a well accepted preclinical ADHD model. Second, PD2005 is as effective as first-line ADHD treatments at improving sustained attention, also a core symptom of ADHD, in another well accepted preclinical ADHD model. Additional Preliminary Studies indicate that PD2005 is effective after oral administration. The proposed studies are the FDA safety and toxicology studies required for submission of a PD2005 Investigational New Drug (IND) application which would allow PD2005 use in humans when approved. All proposed studies will be compiled in Study Reports, submitted to the FDA and discussed with the FDA in a face-to-face Pre-IND meeting to assess PD2005 compliance with FDA ICH M3 IND guidelines.