Development of Novel Inhibitors of Glutamate Carboxypeptidase II

描述(申请人提供)：谷氨酸羧基肽酶II(GCPII)是治疗许多神经系统疾病以及前列腺癌诊断成像和治疗的重要靶点。该酶是一种膜结合的金属肽酶，具有良好的酶活性特征。GCPII抑制剂的开发是一种很有前途的方法，可以用来确定神经保护剂，这些药物可能有助于治疗许多人类疾病，包括创伤性脑损伤、中风、肌萎缩侧索硬化症(ALS)、阿尔茨海默病、帕金森病和其他疾病。虽然几种抑制剂设计已经获得了强大的体外活性，但将此类化合物开发成有用的药物会因药代动力学问题而变得复杂。特别是，GCPII抑制剂通常是高电荷分子，不能口服生物利用和/或不能通过血脑屏障，限制了它们用于治疗神经疾病。这些研究将试图建立新的类别的GCPII抑制剂，预计将是有效的，并具有改善的药代动力学特性。这些研究的另一个目标将是检查等位元变化对抑制剂效力的影响。具体目标：(1)开发新型谷氨酸羧肽酶II的N-羟基谷氨酰基抑制剂(2)采用结构为基础的方法开发新型谷氨酸磺胺类化合物作为谷氨酸羧肽酶II的抑制剂(3)对谷氨酸羧肽酶II抑制剂进行修饰以改善药代动力学。项目简介：与公共健康相关的GCPII抑制剂是一种很有前途的治疗一些重大神经疾病的方法，通过它们与这种酶的相互作用，可以作为神经保护药物。此外，由于GCPII在前列腺癌中过度表达，使用小分子抑制剂靶向该蛋白进行生物成像和癌症治疗是一个非常重要的目标。

DESCRIPTION (provided by applicant): Glutamate carboxypeptidase II (GCPII) is an important target for the treatment of a number of neurological conditions, as well as for diagnostic imaging and treatment of prostate cancer. The enzyme is a membrane- bound metallopeptidase with well-characterized enzymatic activities. Development of GCPII inhibitors is a promising approach for the identification of neuroprotective agents that could be useful to treat a number of human ailments, including traumatic brain injury, stroke, amytrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and other diseases. While several inhibitor designs have obtained potent in vitro activity, developing such compounds into useful drugs is complicated by pharmacokinetic issues. Particularly, GCPII inhibitors are often highly charged molecules that are not orally bioavailable and/or do not pass through the blood brain barrier, limiting their use to treat neurological conditions. These studies will attempt to establish new classes of GCPII inhibitors which are expected to be potent and have improved pharmacokinetic properties. Another goal of these studies will be to examine the effect of isosteric variation on inhibitor potency. Specific Aims: (1) Development of novel N-hydroxyglutamyl inhibitors of glutamate carboxypeptidase II (2) Develop novel glutamyl sulfonamides as inhibitors of glutamate carboxypeptidase II using a structure-based approach (3) Modify glutamate carboxypeptidase II inhibitors to improve pharmacokinetics. Project Narrative: Relevance to public health GCPII inhibitors are a promising treatment for a number of significant neurological conditions, and through their interaction with this enzyme, may serve as neuroprotective drugs. Furthermore, as GCPII is over expressed in prostate cancer, the use of small molecule inhibitors to target for this protein for bioimaging and cancer therapy is a very important goal.