Development of Compounds Targeting xc- for the Treatment of Schizophrenia

描述（由申请人提供）：精神分裂症是一种使人衰弱的疾病，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为600亿美元。高成本的部分原因是缺乏创新，导致治疗非常有限，无效，且依从性差。事实上，在过去的50年里，FDA批准的所有主要的抗精神病药物主要作用于多巴胺和/或血清素受体的功能，不幸的是，这些抗精神病药物产生严重的副作用，对治疗精神分裂症的一些症状无效。该I期SBIR的总体目标是利用主要研究人员实验室的最新进展，暗示谷氨酸释放的高度新颖机制可能有助于精神分裂症。具体来说，半胱氨酸-谷氨酸交换似乎在精神分裂症患者中发生了改变，针对这一机制已被证明在精神分裂症啮齿动物模型中非常有效。为了验证胱氨酸-谷氨酸交换是精神分裂症和其他疾病的有效治疗靶点的假设，我们将合成新的半胱氨酸类似物。接下来，我们将评估新的类似物在体外皮层培养中诱导胱氨酸-谷氨酸交换的能力，并在精神分裂症啮齿动物模型中测试最有希望的化合物对苯环利定产生的感觉运动门控缺陷的正常化能力。通过这种方法确定治疗候选人的能力将为我们的假设提供额外的支持，并为追求胱氨酸类似物作为精神分裂症和其他潜在精神疾病治疗的额外临床前和最终临床研究奠定基础。公共卫生相关性：精神分裂症是一种使人衰弱的疾病，给患者的家庭和照顾者造成了毁灭性的负担，在美国，每年的护理费用高达600亿美元。产生高成本的部分原因是缺乏创新，导致治疗非常有限和无效，并且由于疗效差和出现严重副作用而导致依从性差。这个I期SBIR的主要目标是开发精神分裂症的新疗法。

DESCRIPTION (provided by applicant): Schizophrenia is a debilitating disorder that affects almost 1% of the world's population. The burden on the families and caregivers of patients is immense, and the cost of care in the U.S. is >$60 billion/y. The high costs arise, in part, due to a lack of innovation that has resulted in very limited, ineffective treatments that are associated with poor compliance. Virtually all of the major antipsychotics approved by the FDA in the past fifty years act primarily on dopamine and/or serotonin receptor function, and unfortunately, these antipsychotics produce severe side effects and are ineffective in treating a number of the symptoms of schizophrenia. The overall goal of this Phase I SBIR is to capitalize on recent advances from the principal investigators laboratories implicating a highly novel mechanism of glutamate release that may contribute to schizophrenia. Specifically, cystine-glutamate exchange appears to be altered in schizophrenic patients, and targeting this mechanism has been shown to be highly effective in a rodent model of schizophrenia. In an effort to test the hypothesis that cystine-glutamate exchange represents an effective treatment target for schizophrenia and other disorders, we will synthesize novel cysteine analogs. Next, we will evaluate the capacity of the new analogs to induce cystine-glutamate exchange in cortical cultures in vitro, and test the most promising compounds for their ability to normalize sensorimotor gating deficits produced by phencyclidine in a rodent model of schizophrenia. The ability to identify therapeutic candidates by this approach will provide addition support for our hypothesis, and establish a basis for pursuing additional pre-clinical and ultimately clinical studies of cystine analogs as treatments for schizophrenia and potentially other psychiatric disorders. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating disorder that results in a devastating burden on the families and caregivers of patients and a cost of care in the U.S. of >$60 billion/year. The high costs arise, in part, due to a lack of innovation that has resulted in very limited, ineffective treatments that are associated with poor compliance due to poor efficacy and the emergence of serious side effects. The primary goal of this Phase I SBIR is to develop novel treatments for schizophrenia.