Novel PDE Inhibitors for Depression

治疗抑郁症的新型 PDE 抑制剂

• 批准号: 7053725
• 负责人: Lawrence Paul Wennogle
• 金额: $ 46.38万
• 依托单位: INTRA-CELLULAR THERAPIES, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7053725
• 关键词: AMPA receptors; DARPP; antidepressants; behavior test; behavioral /social science research tag; clinical depression; drug adverse effect; drug discovery /isolation; drug screening /evaluation; enzyme activity; high throughput technology; laboratory mouse; mental disorder chemotherapy; neurotransmitters; nonhuman therapy evaluation; phosphodiesterase inhibitors; phosphodiesterases; phosphoproteins; phosphorylation; psychopharmacology; small molecule

DESCRIPTION (provided by applicant): This proposal is submitted as a Phase II SBIR application, pursuant to our existing Phase I grant, which was funded in response to the NIMH Program Announcement #PA-02-027 entitled: "Pharmacological agents and drugs for mental disorders". The development of new pharmaceuticals for neuropsychiatric disorders is limited by the lack of rapid and effective methods to evaluate potentially useful compounds that arise from primary high throughput screens. As a result of our Phase I grant, ITI has developed a technological platform based on measurements of levels of physiologically-relevant phosphoproteins involved in mediating the effects of neurotransmitters. This platform, based on measurements of changes in protein phosphorylation after treatment of mice in vivo with standard compounds, has been used to profile effects of all known antidepressant drug classes to produce a reference database. Results comprising this database, reviewed in this application, indicate that clinically-efficacious antidepressants characteristically increase the state of phosphorylation in vivo of the dopamine and cAMP-regulated phosphoprotein of Mr=32kDa (DARPP-32) and certain of its downstream targets, including the AMPA receptor subunit, GluR1. The comprehensive goal of this Phase II application is to establish and pursue a drug development program aimed at obtaining a small-molecule inhibitor of PDE1B, the Ca2+/calmodulin-dependent phosphodiesterase 1B, suitable for use as an antidepressant medication, including depression in patients with AIDS or other CNS disorders. To that end we propose the following aims: (I) To develop a screening assay for identifying inhibitors of PDE1B, (II) To screen libraries for the purpose of generating lead compounds, (III) To utilize phospho-profiling methods developed during our Phase I award to assist in optimization of lead compounds, and (IV) To evaluate the efficacy of PDE1B inhibitors as antidepressant medications using a panel of behavioral tests for antidepressant action. Recent results are promising and include: identification of a number of low nanomolar PDE-1B inhibitor "lead" structures, establishment of a high capacity screening assay, and cloning of a full-length human PDE-1B enzyme. In addition to substantial resources already committed, we plan to dedicate further resources in chemistry, and behavioral testing. We have developed a detailed plan to assess potential toxicities associated with PDE-1B inhibitors.

描述（由申请人提供）：本提案作为 II 期 SBIR 申请提交，根据我们现有的 I 期拨款，该拨款是为了响应 NIMH 计划公告 #PA-02-027，标题为：“用于治疗的药物和药物”。精神障碍”。 由于缺乏快速有效的方法来评估初级高通量筛选产生的潜在有用化合物，神经精神疾病新药物的开发受到限制。作为第一阶段资助的结果，ITI 开发了一个基于测量参与介导神经递质作用的生理相关磷蛋白水平的技术平台。该平台基于用标准化合物治疗小鼠体内后蛋白质磷酸化变化的测量，已用于分析所有已知抗抑郁药物类别的效果，以生成参考数据库。本申请中回顾的包含该数据库的结果表明，临床有效的抗抑郁药特征性地增加了 Mr=32kDa (DARPP-32) 的多巴胺和 cAMP 调节的磷蛋白及其某些下游靶标的体内磷酸化状态，包括AMPA 受体亚基，GluR1。该 II 期申请的综合目标是建立并开展一项药物开发计划，旨在获得 PDE1B（Ca2+/钙调蛋白依赖性磷酸二酯酶 1B）的小分子抑制剂，适合用作抗抑郁药物，包括患有抑郁症的患者艾滋病或其他中枢神经系统疾病。为此，我们提出以下目标：(I) 开发一种筛选方法来鉴定 PDE1B 抑制剂，(II) 筛选文库以生成先导化合物，(III) 利用我们阶段开发的磷酸化分析方法我奖励协助优化先导化合物，以及 (IV) 使用一组抗抑郁作用行为测试来评估 PDE1B 抑制剂作为抗抑郁药物的功效。 最近的结果令人鼓舞，包括：鉴定了许多低纳摩尔 PDE-1B 抑制剂“先导”结构，建立了高容量筛选测定法，以及全长人 PDE-1B 酶的克隆。除了已经投入的大量资源外，我们还计划在化学和行为测试方面投入更多资源。我们制定了详细的计划来评估与 PDE-1B 抑制剂相关的潜在毒性。