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和使人衰弱的疾病，影响世界人口的近1%。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。精神分裂症的过度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，在过去的五十年中，FDA批准的所有抗精神病药物都仅作用于多巴胺和/或5-羟色胺受体功能;然而，不幸的是，这些抗精神病药物通常与患者依从性差有关，这是由于疗效不足和出现严重的副作用，包括运动障碍和代谢/心血管副作用。该II期SBIR的总体目标是继续开发我们的新型和创新抗精神病药物，这些药物被认为是当前护理标准的有效和更安全的替代品。具体而言，胱氨酸-谷氨酸交换（系统xc-）似乎在精神分裂症患者中发生了改变，我们先前在I期SBIR中已经表明，在啮齿动物精神分裂症模型中，靶向这种机制非常有效。目前的拨款申请旨在利用这些发现和我们的第一阶段SBIR基金，这些基金用于发现和研究一系列新的分子，这些分子被设计成靶向系统xc-。我们的先导小分子是体外皮质培养物中系统xc-的有效驱动剂，我们已经在精神分裂症的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指导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其他潜在精神疾病的新型治疗方法。 公共卫生关系：精神分裂症是一种慢性的，使人衰弱的疾病，会给患者的家庭和照顾者带来毁灭性的负担。美国每年的医疗费用超过600亿美元。高成本的产生部分是由于缺乏创新，导致治疗选择非常有限，由于疗效差和出现严重副作用，这些治疗选择通常与依从性差有关。这个第二阶段SBIR项目的目标是充分表征由第一阶段资助的工作中确定的主要药物开发候选药物，着眼于开发新型和创新的抗精神病药物。