Development of Novel Inhibitors of Glutamate Carboxypeptidase II

新型谷氨酸羧肽酶II抑制剂的研制

基本信息

批准号：
7777336
负责人：
Marc O Anderson
金额：
$ 14.84万
依托单位：
SAN FRANCISCO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777336
关键词：
Active Sites Address Alzheimer&apos s Disease Amides Appointment Area Binding Bioavailable Biological Availability Biological Models Blood - brain barrier anatomy CCL7 gene Charge Chemical Structure Chimeric Proteins Clinical Collaborations Complement Comprehensive Cancer Center Computers Consult Coupled Crystallography Development Diagnostic Imaging Disease Docking Drug Delivery Systems Drug Design Drug Kinetics Educational Curriculum Educational process of instructing Educational workshop Enzymes Event Faculty Feedback Funding Future Generations Glutamate Carboxypeptidase II Glutamates Goals Grant Growth HIV Envelope Protein gp41 Human Hydrolysis Hydroxamic Acids Hydroxylamine Imaging Techniques Insulin-Like Growth Factor Receptor Knowledge Label Laboratories Lassa Fever Learning Literature Malignant neoplasm of prostate Manuscripts Membrane Mentors Metalloproteases Methods Molecular Genetics Motivation Natural Sciences Neurologic Neuroprotective Agents Nordihydroguaiaretic Acid Oral Organic Chemistry Orphan Disease Paper Parkinson Disease Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Philosophy Positioning Attribute Postdoctoral Fellow Primary Lateral Sclerosis Process Property Protease Inhibitor Proteins Proteolysis Public Health Publications Publishing Radio Reaction Receptor Protein-Tyrosine Kinases Recruitment Activity Research San Francisco Scientist Secure Stroke Structure Students Sulfonamides Techniques Traumatic Brain Injury Universities Variant Viral Fusion Proteins Work Zinc absorption analog antitumor drug base bioimaging cancer therapy carboxyl group career career development design drug development experience fascinate functional group graduate student hydroxamate improved in vitro activity in vivo inhibitor/antagonist instructor lectures malignant breast neoplasm member next generation novel operation programs scaffold skills small molecule symposium text searching tool

项目摘要

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.

描述（由申请人提供）：谷氨酸羧肽酶 II (GCPII) 是治疗多种神经系统疾病以及前列腺癌的诊断成像和治疗的重要靶标。该酶是一种膜结合金属肽酶，具有明确的酶活性。 GCPII 抑制剂的开发是鉴定神经保护剂的一种有前途的方法，可用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获得有效的体外活性，但将此类化合物开发成有用的药物由于药代动力学问题而变得复杂。特别地，GCPII抑制剂通常是高电荷分子，不能口服生物利用和/或不能穿过血脑屏障，限制了它们在治疗神经系统疾病中的用途。这些研究将尝试建立新类别的 GCPII 抑制剂，这些抑制剂有望有效并具有改善的药代动力学特性。这些研究的另一个目标是检查等排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-羟基谷氨酰抑制剂 (2) 使用基于结构的方法开发新型谷氨酰磺酰胺作为谷氨酸羧肽酶 II 的抑制剂 (3) 修饰谷氨酸羧肽酶 II 抑制剂以改善药代动力学。项目叙述：与公共卫生的相关性 GCPII 抑制剂是治疗许多重要神经系统疾病的一种有前途的治疗方法，并且通过它们与这种酶的相互作用，可以充当神经保护药物。此外，由于 GCPII 在前列腺癌中过度表达，因此使用小分子抑制剂来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。