Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia

描述(申请人提供)：目前可用的精神分裂症抗精神病药物不能有效地治疗与疾病相关的所有主要症状，并与一些剂量限制的不良反应有关。因此，迫切需要开发新的治疗药物来治疗精神分裂症，比现有的药物具有更广泛的疗效和更少的不良反应。我们提出的研究旨在发现和优化治疗精神分裂症的新药候选，这些药物在机械上与现有的抗精神病药物无关，并有可能在治疗这种疾病的所有主要症状群方面提供疗效。这些计划中最先进的是发现抑制甘氨酸转运蛋白1 GlyT1的新化合物。甘氨酸是谷氨酸受体A/-甲基-D-天冬氨酸(NMDA)亚型的共同激动剂，在维持NMDA受体激活的活性依赖性的同时，为增强NMDA受体的功能提供了一种很好的途径。许多临床和动物研究表明，GlyTI抑制剂在治疗精神分裂症方面具有令人兴奋的潜力。到目前为止，我们已经优化了GlyTI抑制剂的新型支架，具有良好的药代动力学和脑渗透特性，在动物模型中具有强大的疗效，并且没有显著的毒性。第二个项目的重点是发现和优化高选择性的M_1乙酰胆碱受体的别固醇激动剂。我们已经建立了一种新的方法，通过靶向变构部位来开发高选择性的M1 M受体激动剂，并在预测精神分裂症治疗效果的动物模型中证明了这些化合物具有强大的疗效。ML和GlyTI计划都是基于动物模型和令人兴奋的临床数据的强有力的验证，这些数据为追求这些新的目标提供了支持。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。我们将从GlyTI抑制剂的先导优化开始，然后是HIT-TC-先导和ML变构激动剂的先导优化，目标是将与这些药物相互作用的分子推进到为临床前和临床开发做好准备的阶段。最后，我们有更多目标的管道，我们有化学上不同的验证命中和早期药物线索，准备进行全面的线索优化工作。虽然没有明确包含在本应用程序中，但这提供了一个强大的发现管道，这对本计划的未来发展方向将非常重要。 公共卫生评论：该计划的主要目标是发现新的候选药物，这些药物最终将进入治疗精神分裂症的临床测试。如果成功，这一努力产生的新型药物可能会在治疗这种疾病方面取得根本性突破，并可能极大地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.