Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia

范德比尔特 NCDDDG 发现精神分裂症新疗法

基本信息

批准号：
8423776
负责人：
P Jeffrey Conn
金额：
$ 180.53万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-19 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423776
关键词：
Adverse effects Affect Agonist Allosteric Site Animal Model Animals Antipsychotic Agents Brain Characteristics Chemicals Clinical Clinical Data Clinical Research D Aspartate Data Dependence Development Disease Disease Clusterings Dopamine Dose-Limiting Drug Kinetics Excretory function Future GLYT1 Glutamate Receptor Glutamates Glycine Goals Impairment Lead Mental disorders Metabolism Muscarinic Acetylcholine Receptor N-Methyl-D-Aspartate Receptors N-Methylaspartate Penetration Pharmaceutical Preparations Population Property Public Health Receptor Activation Schizophrenia Series Signal Transduction Staging Symptoms System Therapeutic Agents Toxic effect Validation Work absorption base drug candidate effective therapy human CHRM1 protein improved in vivo industry partner inhibitor/antagonist monoamine novel novel strategies novel therapeutics pre-clinical programs receptor receptor function research clinical testing scaffold standard of care transmission process

项目摘要

DESCRIPTION (provided by applicant): Currently available antipsychotics for schizophrenia are not effective for the treatment of all major symptoms associated with the disease and are associated with a number of dose-limiting adverse effects. Thus, there is a critical need to develop novel therapeutic agents for treatment of schizophrenia that have broader efficacy and fewer adverse effects than currently available medications. We propose studies aimed at discovery and optimization of novel drug candidates for treatment of schizophrenia that are mechanistically unrelated to currently available antipsychotic agents and have the potential to provide efficacy in treatment of all major symptom clusters of this disease. The most advanced of these programs is focused on discovery of novel compounds that inhibit the glycine transporter 1, GlyT1. Glycine is a co-agonist with glutamate at the A/-methyl-D-aspartate (NMDA) subtype of glutamate receptors and provides an excellent approach to increasing NMDA receptor function while maintaining activity dependence of NMDA receptor activation. A number of clinical and animals studies suggest that GlyTI inhibitors have exciting potential for treatment of schizophrenia. To date, we have optimized novel scaffolds of GlyTI inhibitors with excellent pharmacokinetic and brain penetration profiles, robust efficacy in animal models, and lack significant toxicity. A second program is focused on discovery and optimization of highly selective allcsteric agonists of the M1 muscarinic acetylcholine receptor. We have established a novel approach to development of highly selective agonists of the M1 muscarinic acetylcholine receptor by targeting allosteric sites and have shown that these compounds have robust efficacy in animal models that predict efficacy in treatment of schizophrenia. Both the Ml and GlyTI programs are based on strong validation from animal models and exciting clinical data that provide support for pursuing these novel targets. Our overall objective is to optimize drug candidates that interact with each of these targets. Ultimately, we will work with industry partners to develop these drug candidates in clinical studies. We will begin with lead optimization of GlyTI inhibitors, followed by hit-tc-lead and lead optimization of Ml allosteric agonists with a goal of advancing molecules that interact with each of these to a stage where they are ready for preclinical and clinical development. Finally, we have a pipeline of additional targets for which we have chemically diverse verified hits and early drug leads that are poised for full lead optimization efforts. While not specifically included in this application, this provides a robust discovery pipeline that will be important for the future directions of this program. PUBLIC HEALTH REVELANCE: The major goal of this program is to discover novel drug candidates that will ultimately advance into clinical testing for treatment of schizophrenia. If successful, novel drugs that come from this effort could lead to a fundamental breakthrough in the treatment of this disorder and could dramatically improve the standard of care for this devastating disorder.

描述（由申请人提供）：目前可用于精神分裂症的抗精神病药对治疗与该疾病有关的所有主要症状无效，并且与许多剂量限制的不良反应有关。因此，与目前可用的药物相比，要开发新型治疗剂来开发新型治疗剂，以治疗具有更广泛疗效和更少的不良反应的精神分裂症。我们提出了旨在发现和优化新型药物治疗精神分裂症的研究，这些药物与当前可用的抗精神病药无关，并有可能在治疗该疾病的所有主要症状簇方面提供功效。这些程序中最先进的集中在于发现抑制甘氨酸转运蛋白1 Glyt1的新型化合物。甘氨酸是与谷氨酸受体的A/甲基-D-天冬氨酸（NMDA）亚型的谷氨酸共同振动剂，并为增加NMDA受体功能提供了出色的方法，同时维持NMDA受体活化的活性依赖性。许多临床和动物研究表明，Glyti抑制剂具有精神分裂症治疗的令人兴奋的潜力。迄今为止，我们已经优化了具有出色的药代动力学和脑渗透谱，动物模型中强大的疗效以及缺乏明显毒性的新型Glyti抑制剂的新型脚手架。第二个程序的重点是发现和优化M1毒蕈碱乙酰胆碱受体的高度选择性的全肠激动剂。我们通过靶向变构位点建立了一种新型的M1毒蕈碱乙酰胆碱受体的激动剂开发的新方法，并表明这些化合物在预测精神分裂症治疗功效的动物模型中具有强大的效率。 ML和Glyti程序均基于动物模型的强烈验证和令人兴奋的临床数据，这些数据为追求这些新型目标提供了支持。我们的总体目标是优化与每个目标相互作用的候选药物。最终，我们将与行业合作伙伴合作，在临床研究中开发这些候选者。我们将从Glyti抑制剂的铅优化开始，然后进行HIT-TC-LEAD和ML变构激动剂的铅优化，其目的是推进与每个阶段相互作用的分子，以准备临床前和临床发育。最后，我们有一系列其他目标的管道，我们拥有化学多样的验证命中率和早期药物铅，这些铅有望进行全面的铅优化工作。虽然不是在本应用程序中特别包含在此应用程序中，但它提供了强大的发现管道，这对于该程序的未来方向很重要。公共卫生的启示：该计划的主要目标是发现新的候选药物，最终将进步进行精神分裂症治疗的临床测试。如果成功的话，这项努力带来的新型药物可能会导致这种疾病的治疗方面的基本突破，并可以大大提高这种毁灭性疾病的护理标准。