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

基本信息

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
项目类别：
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

项目摘要

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）：焦虑和抑郁在患有神经发育障碍（包括自闭症谱系障碍（ASD）和精神分裂症）的患者中普遍存在，这些共病障碍会导致异常的社交互动和人际沟通缺陷，从而加剧社会孤立。值得注意的是，超过 40% 的 ASD 患者至少患有一种焦虑症，而大多数精神分裂症患者都患有抑郁症。据报道，抗抑郁药物对这些患者的效果甚微，并且常常会严重加剧多动、攻击性和易怒性，有效改善这些神经发育障碍患者情绪而不促进多动或攻击性的新治疗药物将非常有效。在此，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 (PDE2) 抑制剂，这是一种治疗临床前动物焦虑和抑郁的新型临床前靶点。测试，作为治疗神经发育疾病中情绪障碍的一流疗法，PDE2 酶可控制涉及认知和情绪的大脑区域（包括皮层、海马和纹状体）的环核苷酸、cAMP 和 cGMP 水平。在动物行为范式中具有类似抗焦虑和抗抑郁的功效，尽管这些化合物通常具有较差的生物利用度并且表现出有限的脑通透性，阻碍了它们的临床开发细胞内疗法。 Inc (ITI) 是一家临床阶段制药公司，拥有成熟的药物发现平台和发现蛋白磷酸二酯酶 (PDE1) 小分子抑制剂的专业知识，已发现该酶的小分子抑制剂，具有 nM 效力、良好的选择性（与其他 PDE 相比）家族），并且与已发表的化合物相比具有优异的生物利用度和脑渗透性。ITI 建议与纽约州立大学布法罗分校的专家 James M. O'Donnell 和 Ying Xu 博士合作。表征 PDE2 抑制的抗焦虑和抗抑郁作用，以测试这些分子的行为功效，我们计划优化先导 PDE2 抑制剂，使其具有相当或更好的效力（低 nM）和选择性（与其他 PDE 家族酶相比），并改善口服生物利用度和代谢。与已发表的化合物（例如 BAY60-7550）相比的稳定性将在一组抗焦虑和抗抑郁范例中进行测试。 Ying/O'Donnell 实验室将选择具有卓越功效的分子，以便在未来的 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，以研究其效用（和潜在的方面）。 PDE2 抑制剂在动物模型中的作用与 ASD 等神经发育疾病的相关特征和其他特征（包括社会行为和多动）有关。