Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia

描述（由申请方提供）：目前可用的精神分裂症抗精神病药不能有效治疗与该疾病相关的所有主要症状，并且与许多剂量限制性不良反应相关。因此，迫切需要开发用于治疗精神分裂症的新型治疗剂，其具有比目前可用的药物更广泛的功效和更少的副作用。我们提出的研究旨在发现和优化治疗精神分裂症的新型候选药物，这些药物与目前可用的抗精神病药物在机制上无关，并有可能在治疗这种疾病的所有主要症状群中提供疗效。这些项目中最先进的是发现抑制甘氨酸转运蛋白1（GlyT 1）的新型化合物。甘氨酸是谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）亚型处的谷氨酸的共激动剂，并且提供了增加NMDA受体功能同时维持NMDA受体活化的活性依赖性的极好方法。许多临床和动物研究表明，GlyTI抑制剂具有治疗精神分裂症的令人兴奋的潜力。迄今为止，我们已经优化了GlyTI抑制剂的新型支架，其具有优异的药代动力学和脑渗透特性，在动物模型中具有稳健的功效，并且没有显著的毒性。第二个项目集中于发现和优化M1毒蕈碱乙酰胆碱受体的高选择性变构激动剂。我们已经建立了一种新的方法，通过靶向变构位点来开发M1毒蕈碱乙酰胆碱受体的高选择性激动剂，并且已经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稳健的功效。Ml和GlyTI计划都是基于来自动物模型的强有力的验证和令人兴奋的临床数据，这些数据为追求这些新靶点提供了支持。我们的总体目标是优化与这些靶点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药物。我们将开始以GlyTI抑制剂的先导物优化，随后是Ml变构激动剂的hit-tc-先导物和先导物优化，目标是将与这些中的每一种相互作用的分子推进到它们准备用于临床前和临床开发的阶段。最后，我们有一个额外的目标管道，我们有化学多样的验证命中和早期药物线索，准备充分的铅优化工作。虽然没有特别包括在本申请中，但这提供了一个强大的发现管道，这对本程序的未来方向非常重要。 公共卫生部门：该计划的主要目标是发现新的候选药物，最终将进入治疗精神分裂症的临床试验。如果成功，来自这一努力的新药可能会导致这种疾病治疗的根本突破，并可能大大提高这种毁灭性疾病的护理标准。

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.