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: 8698210
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698210
• 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.

描述（由申请人提供）：精神分裂症是一种长期衰弱的疾病，影响了世界近1％的人口。患者的家庭和看护人的负担巨大，美国每年的护理费用大于600亿美元。精神分裂症的高昂财务压力在很大程度上是由于缺乏创新而导致的，导致了非常有限，无效且耐受性不佳的治疗选择。实际上，FDA在过去的五十年中批准的所有抗精神病药都专门针对多巴胺和/或5-羟色胺受体功能；但是，不幸的是，由于功效不足以及包括运动障碍和代谢 /心血管副作用在内的严重副作用的出现，这些抗精神病药通常与患者依从性不佳有关。这一II阶段SBIR的总体目标是继续开发我们的新颖和创新的抗精神病药物，这些药物被认为是当前护理标准的有效替代品。具体而言，精神分裂症患者的胱氨酸 - 谷氨酸交换（系统XC-）似乎正在改变，并且我们以前在我们的I期SBIR中显示，靶向这种机制在精神分裂症的啮齿动物模型中非常有效。当前的赠款应用程序旨在利用这些发现以及我们的I期SBIR资金，这些基金被用来发现并研究了一系列新型的分子，这些分子设计为靶向系统XC-。我们的铅小分子是体外皮质培养物中系统XC-的有效驱动因素，我们已经证实了精神分裂症啮齿动物模型中的临床前效应。我们建议扩大这些发现，并进一步描述我们在索引安全药理学和毒理学研究中的铅分子，并着眼于开发一种新型的治疗方法，用于治疗精神分裂症和潜在的其他精神疾病。