Targeting System Xc- for the Treatment of Schizophrenia

靶向系统 Xc- 用于治疗精神分裂症

• 批准号: 8397352
• 负责人: DAVID A BAKER
• 金额: $ 60万
• 依托单位: PROMENTIS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397352
• 关键词: Acetylcysteine; Address; Adverse effects; Affect; Agranulocytosis; Antipsychotic Agents; Applications Grants; Award; Behavior; Brain; Canis familiaris; Cardiovascular system; Caring; Characteristics; Chemistry; Chronic; Cysteine; Cystine; Data; Development; Disease; Dopamine; Drug Design; Drug Kinetics; Engineering; Evaluation; Exhibits; Eye; FDA approved; Family Caregiver; Functional disorder; Funding; Glutamates; Glycine; Goals; Government; Grant; Human; In Vitro; Lead; Measures; Mental disorders; Metabolic; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Oral; Patients; Persons; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Population; Process; Prodrugs; Property; Quality of life; Rattus; Rodent; Rodent Model; Safety; Schizophrenia; Seizures; Series; Signal Transduction; Site; Small Business Innovation Research Grant; Source; Structure-Activity Relationship; Sulfhydryl Compounds; Symptoms; Synapses; System; Telemetry; Testing; Tissues; United States; Work; brain tissue; compliance behavior; cost; design; drug development; drug discovery; extracellular; improved; innovation; meetings; motor impairment; neurodevelopment; neurotransmitter release; novel; novel therapeutic intervention; pre-clinical; preclinical efficacy; receptor function; research study; respiratory; safety study; serotonin receptor; small molecule; therapeutic target; tool; transmission process; uptake

DESCRIPTION (provided by applicant): Schizophrenia is a chronic and debilitating disorder that impacts nearly 1% of the world's population. The burden on the families and caregivers of patients is immense, with the cost of care in the United States being greater than $60 billion annually. The exorbitant financial strain of schizophrenia arises, in large part, to a lack of innovation that has resulted in very limited, ineffective and poorly-tolerated treatment options. Virtually all of the antipsychotics approved by the FDA in the past fifty years act exclusively on dopamine and/or serotonin receptor function; however, unfortunately, these antipsychotics are routinely associated with poor patient compliance due to inadequate efficacy and the emergence of serious side effects including motor impairments and metabolic / cardiovascular side effects. The overall goal of this Phase II SBIR is to continue the development of our novel and innovative antipsychotic medications that are proposed to be an effective and safer alternative to the current standards of care. Specifically, cystine-glutamate exchange (system xc-) appears to be altered in schizophrenic patients, and we have shown previously in our Phase I SBIR that targeting this mechanism is highly effective in a rodent model of schizophrenia. This current grant application is designed to capitalize on these findings and our Phase I SBIR funds that were employed to discover and investigate a novel series of molecules engineered to target system xc-. Our lead small molecules are potent drivers of system xc- in cortical cultures in vitro and we have confirmed preclinical proof-of-efficacy in rodent models of schizophrenia. We propose to expand on these findings and further characterize our lead molecule in IND-directed safety pharmacology and toxicology studies, with an eye towards developing a novel therapeutic approach for the treatment of schizophrenia and potentially other psychiatric disorders. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic, debilitating disorder that results in a devastating burden on the families and caregivers of patients. The cost of care in the United States is in excess of $60 billion a year. The high costs arise, in part, due to a lack of innovatin that has resulted in very limited treatment options that are routinely associated with poor compliance due to poor efficacy and the emergence of serious side effects. The goal of this Phase II SBIR project is to fully characterize lead drug development candidates identified in work funded by the Phase I grant with an eye towards the development of novel and innovative antipsychotic agents.

描述（由申请人提供）：精神分裂症是一种慢性且使人衰弱的疾病，影响着世界上近 1% 的人口。患者家属和护理人员的负担是巨大的，美国每年的护理费用超过 600 亿美元。精神分裂症造成的巨大经济压力在很大程度上是由于缺乏创新导致治疗选择非常有限、无效和耐受性差。事实上，过去五十年来 FDA 批准的所有抗精神病药都专门作用于多巴胺和/或血清素受体功能；然而，不幸的是，由于疗效不足以及出现包括运动障碍和代谢/心血管副作用在内的严重副作用，这些抗精神病药通常与患者依从性差有关。 II 期 SBIR 的总体目标是继续开发我们的新颖和创新抗精神病药物，这些药物被提议成为当前护理标准的有效且更安全的替代品。具体来说，胱氨酸-谷氨酸交换（系统xc-）在精神分裂症患者中似乎发生了改变，我们之前在第一阶段SBIR中已经证明，针对这一机制在精神分裂症啮齿动物模型中非常有效。目前的拨款申请旨在利用这些发现和我们的第一阶段 SBIR 资金，这些资金用于发现和研究针对目标系统 xc- 设计的一系列新型分子。我们的先导小分子是体外皮质培养中 xc- 系统的有效驱动因素，并且我们已经在精神分裂症啮齿动物模型中证实了临床前疗效证明。我们建议扩展这些发现，并在 IND 导向的安全药理学和毒理学研究中进一步表征我们的先导分子，着眼于开发一种治疗精神分裂症和潜在其他精神疾病的新治疗方法。 公共卫生相关性：精神分裂症是一种慢性、使人衰弱的疾病，给患者的家人和护理人员带来毁灭性的负担。美国每年的医疗费用超过 600 亿美元。造成高昂费用的部分原因是缺乏创新，导致治疗选择非常有限，而这些选择通常因疗效差和出现严重副作用而导致依从性差。该 II 期 SBIR 项目的目标是全面描述 I 期拨款资助的工作中确定的先导药物开发候选药物的特征，着眼于开发新颖和创新的抗精神病药物。