ADHD Therapeutic: PD2005 DA Transport Inhibitor

描述（由申请人提供）： SBIR 1期临床前研究证明了我们的专利化合物PD 2005治疗注意力缺陷/多动障碍（ADHD）的疗效。PD 2005是一种选择性多巴胺（DA）转运抑制剂，P2 D正在开发用于治疗ADHD。美国儿科学会将非选择性DA转运抑制剂哌甲酯和安非他明确定为ADHD唯一批准的一线治疗药物。这些一线治疗是主要给儿童服用的附表二滥用药物。相比之下，在国家药物滥用研究所（NIDA）进行的研究中，PD 2005没有滥用潜力。拟议研究的长期目标是开发一种安全有效、滥用可能性有限的ADHD治疗方法（非计划或计划IV）。 PD 2005是苯托品类似物。苯扎托品是一种高亲和力DA转运抑制剂，FDA发现其安全有效，临床使用超过30年。苯扎托品没有明显的滥用潜力，是一种非附表药物。不幸的是，苯扎托品的临床显著的抗胆碱能副作用排除了其作为ADHD治疗的用途。广泛的铅优化研究已经进行了我们的专利库苯托品类似物。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副作用，包括苯扎托品的抗胆碱能心血管副作用（心动过速）特征。此外，由美国食品药品监督管理局（FDA）药物评价中心（CDER）委托进行了一项PD 2005安全性和毒理学研究。在这些FDA计算研究中，未发现PD 2005在主要器官系统中的致癌性、致畸性、致突变性或毒理学。这些数据突出了PD 2005 SBIR 1期研究的安全性特征改善，证明PD 2005与目前的一线ADHD治疗一样有效。首先，在公认的临床前ADHD模型中，PD 2005在改善工作记忆（ADHD的核心症状）方面与一线ADHD治疗一样有效。其次，在另一个公认的临床前ADHD模型中，PD 2005在改善持续注意力方面与一线ADHD治疗一样有效，这也是ADHD的核心症状。其他初步研究表明，PD 2005口服给药后有效。 拟定研究是提交PD 2005研究性新药（IND）申请所需的FDA安全性和毒理学研究，该申请在获得批准后将允许PD 2005用于人体。所有拟定研究将汇编为研究报告，提交给FDA，并在面对面的IND前会议上与FDA进行讨论，以评估PD 2005是否符合FDA ICH M3 IND指南。 公共卫生相关性：美国儿科学会将哌醋甲酯和安非他明确定为唯一批准的注意力缺陷/多动障碍（ADHD）的一线治疗药物。这些一线治疗是主要给儿童服用的附表二滥用药物。拟议研究的目标是开发一种新的ADHD治疗方法，与目前的一线治疗方法一样有效，但副作用减少，包括没有滥用潜力。

DESCRIPTION (provided by applicant): 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) characteristi 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. PUBLIC HEALTH RELEVANCE: The American Academy of Pediatrics identifies methylphenidate and amphetamine as the only approved first-line treatments for Attention Deficit/Hyperactivity Disorder (ADHD). These first-line treatments are Schedule II drugs of abuse administered primarily to children. The goal of the proposed studies is to develop a new ADHD treatment as effective as current first-line treatments but with reduced side effects including no abuse potential.