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PD2005的疗效， 用于治疗注意力缺陷/多动障碍(ADHD)。PD2005是一种选择性多巴胺 治疗ADHD的转运蛋白抑制剂--P2D。美国科学院 儿科确认非选择性DA转运抑制剂哌醋甲酯和苯丙胺是 只批准了ADHD的一线治疗。这些一线治疗是二类滥用药物。 主要用于儿童。相比之下，PD2005在研究中没有显示出滥用的可能性 在国家药物滥用研究所(NIDA)进行。拟议研究的长期目标是 开发安全有效、滥用潜力有限的ADHD治疗方法(非计划或计划 四)。 PD2005是苯并托品类似物。苯妥拉平是一种高亲和力的DA转运抑制剂，被发现是安全的 并被FDA有效并在临床上使用了30多年。苯妥拉平显示没有明显的意义 可能会滥用，是一种不符合规定的药物。不幸的是，苯并托品的临床意义 胆碱能副作用使其不能用于ADHD治疗。广泛的销售线索优化研究 都是用我们专有的苯并托品类似物库进行的。初步研究表明 我们的先导化合物PD2005没有表现出抗胆碱能副作用，包括抗胆碱能 苯妥拉平的胆碱能心血管副作用(心动过速)。此外，一款PD2005 安全和毒理学研究是由美国食品和药物管理局委托进行的 (FDA)药物评价中心(CDER)。无PD2005致癌、致畸、致突变或 在这些FDA的计算研究中发现了主要器官系统的毒理学。这些数据突出显示 改进后的PD2005安全配置文件 SBIR第一阶段研究表明，PD2005与目前的一线ADHD一样有效 治疗。首先，PD2005在改善工作记忆方面与一线ADHD治疗一样有效， 核心ADHD症状，在公认的临床前ADHD模型中。其次，PD2005与 ADHD的一线治疗是为了改善持续注意力，这也是ADHD的核心症状 临床前ADHD模型被广泛接受。更多初步研究表明，PD2005是有效的 口服后给药。 建议的研究是FDA安全和毒理学研究，要求提交 PD2005研究新药(IND)申请，允许在以下情况下在人类身上使用PD2005 批准了。所有建议的研究都将汇编在研究报告中，提交给FDA并讨论 与FDA进行面对面的IND前会议，以评估PD2005是否符合FDA ICH M3 IND 指导方针。

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.