Development of PDE2 Inhibitors for Treatment of Anxiety/Depression in Autism/Schizophrenia

开发用于治疗自闭症/精神分裂症焦虑/抑郁的 PDE2 抑制剂

• 批准号: 9129932
• 负责人: GRETCHEN L SNYDER
• 金额: $ 34.81万
• 依托单位: INTRA-CELLULAR THERAPIES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129932
• 关键词: Address; Adverse effects; Affect; Aggressive behavior; Agitation; Animal Model; Animal Testing; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Autistic Disorder; Behavioral; Behavioral Paradigm; Binding; Bioavailable; Biological Assay; Biological Availability; Biotechnology; Brain; Brain region; Buffaloes; CREB1 gene; Cell Culture Techniques; Cells; Central Nervous System Diseases; Clinical; Cognition; Cognition Disorders; Cognitive; Corpus striatum structure; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Data; Development; Disease; Drug Targeting; Enzymes; Exhibits; Family; Family member; Future; Genes; Half-Life; Hippocampus (Brain); Hyperactive behavior; In Vitro; Lead; Libraries; Literature; Mental Depression; Metabolic; Metabolism; Modeling; Molecular Target; Monitor; Mood Disorders; Moods; Motor Activity; Mus; Neurodevelopmental Disorder; New York; Oral; Patients; Penetrance; Penetration; Permeability; Personal Communication; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphodiesterase Inhibitors; Plasma; Preparation; Principal Investigator; Program Development; Proteins; Publishing; RNA Splicing; Reporting; Rodent; Safety; Schizophrenia; Scientist; Sedation procedure; Selective Serotonin Reuptake Inhibitor; Signal Transduction; Small Business Innovation Research Grant; Social Behavior; Social Interaction; Social isolation; Staging; Stress; Tail Suspension; Testing; Therapeutic; Therapeutic Agents; Universities; Variant; Vulnerable Populations; Work; antidepressant effect; anxiety symptoms; anxiety treatment; anxiety-like behavior; autism spectrum disorder; base; behavior test; biophysical properties; clinical investigation; depressive symptoms; drug candidate; drug discovery; experience; feeding; improved; inhibitor/antagonist; innovation; new therapeutic target; novel; novel therapeutics; phosphoric diester hydrolase; pre-clinical; programs; public health relevance; research clinical testing; restraint stress; scaffold; screening; small molecule; small molecule inhibitor; small molecule therapeutics; symptom treatment; tool; vasodilator-stimulated phosphoprotein

 DESCRIPTION (provided by applicant): Anxiety and depression are prevalent in patients affected by neurodevelopmental disorders, including autism spectrum disorders (ASD) and schizophrenia. These co-morbid disorders contribute to abnormal social interaction and deficits in interpersonal communication that intensify the social isolation in patients. It is noteworthy tht over 40% of ASD patients experience at least one anxiety disorder while co-morbid depression is present in the majority of schizophrenia patients. Significantly, current anti- depressant medications are reported to be minimally-effective in these patients and, often, seriously exacerbate hyperactivity, aggression, and irritability. New therapeutic agents that effectively improve mood in patients with these neurodevelopmental disorders, without promoting hyperactivity or aggression, would be highly significant and are urgently needed. Here, we propose a one-year Phase I SBIR project to advance inhibitors of phosphodiesterase-2 (PDE2), a novel preclinical target for treatment of anxiety and depression into preclinical animal testing, as first-in-class treatments for mood disorders in neurodevelopmental disease. The PDE2 enzyme controls levels of cyclic nucleotides, cAMP and cGMP in brain regions involved in cognition and mood, including cortex, hippocampus, and striatum. Published tool compounds inhibiting PDE2 activity display antianxiety-like and antidepressant-like efficacy in animal behavioral paradigms, though these compounds have generally poor bioavailability and exhibit limited brain permeability, hindering their clinical development, to date. Intra-Cellular Therapies Inc (ITI), a clinical-stage pharmaceutical company with an established drug discovery platform and expertise in discovering small-molecule inhibitors for protein phosphodiesterases (PDE1), has discovered small molecule inhibitors of the enzyme with nM potency, good selectivity (versus other PDE families), and superior bioavailability and brain penetrance versus published compounds. ITI proposes to collaborate with Drs. James M. O'Donnell and Ying Xu at the SUNY at Buffalo, experts in the characterization of antianxiety and antidepressant effects of PDE2 inhibition, to test the behavioral efficacy of these molecules. We plan to optimize lead PDE2 inhibitors with comparable or better potency (low nM) and selectivity (versus other PDE family enzymes) and improved oral bioavailability and metabolic stability compared with to published compounds (e.g., BAY60-7550). Up to five compounds will be tested in a panel of antianxiety and antidepressant paradigms in the Ying/O'Donnell lab to select molecules with superior efficacy for advancement into a preclinical development program in a future Phase II SBIR application. We propose to extend these studies, if successful, during a Phase II project to investigate the utility (and potential side effects) of PDE2 inhibitors in animal models relevant t other features of neurodevelopmental diseases such as ASD, including social behavior and hyperactivity.

 描述（由申请人提供）：焦虑和抑郁在受神经发育障碍影响的患者中普遍存在，包括自闭症谱系障碍（ASD）和精神分裂症。这些共病障碍导致异常的社会交往和人际交往的缺陷，加剧了患者的社会孤立。值得注意的是，超过40%的ASD患者经历至少一种焦虑障碍，而大多数精神分裂症患者存在共病抑郁。值得注意的是，据报道，目前的抗抑郁药物在这些患者中的效果最小，并且通常会严重加剧多动、攻击性和易怒。新的治疗药物，有效地改善这些神经发育障碍患者的情绪，而不促进多动症或侵略性，将是非常重要的，迫切需要。在这里，我们提出了一个为期一年的I期SBIR项目，以推进磷酸二酯酶-2（PDE 2）抑制剂的临床前动物试验，PDE 2是一种治疗焦虑和抑郁症的新型临床前靶点， 作为神经发育疾病中情绪障碍的一流治疗方法。PDE 2酶控制认知和情绪相关脑区（包括皮质、海马和纹状体）的环核苷酸、cAMP和cGMP水平。迄今为止，已发表的抑制PDE 2活性的工具化合物在动物行为范式中显示出抗焦虑和抗抑郁的功效，尽管这些化合物的生物利用度通常较差，并且脑渗透性有限，阻碍了它们的临床开发。细胞内治疗 Inc（ITI）是一家临床阶段的制药公司，拥有成熟的药物发现平台和发现蛋白质磷酸二酯酶（PDE 1）小分子抑制剂的专业知识，已经发现了具有nM效力，良好选择性（相对于其他PDE家族）和上级生物利用度和脑转移率的酶小分子抑制剂。ITI建议与James M.纽约州立大学布法罗分校的奥唐纳和徐颖是研究PDE 2抑制剂抗焦虑和抗抑郁作用的专家，他们测试了这些分子的行为功效。我们计划优化具有可比或更好的效力（低nM）和选择性（相对于其他PDE家族酶）以及与公开的化合物（例如，BAY60-7550）。多达五种化合物将在Ying/奥唐纳实验室的一组抗焦虑和抗抑郁范例中进行测试，以选择具有上级功效的分子，用于在未来的II期SBIR应用中进入临床前开发计划。如果成功，我们建议在II期项目期间扩展这些研究，以研究PDE 2抑制剂在与神经发育疾病（如ASD）的其他特征（包括社会行为和多动）相关的动物模型中的效用（和潜在副作用）。