Medicinal Chemistry

药物化学

• 批准号: 7988517
• 负责人: CRAIG LINDSLEY
• 金额: $ 63.5万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/7988517
• 关键词: Pharmaceutical Chemistry; Schizophrenia; novel

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 allosteric 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.

描述（由申请人提供）：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副作用相关。因此，迫切需要开发用于治疗精神分裂症的新型治疗剂，其比目前可用的药物具有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候选药物，这些候选药物在机制上与目前可用的抗精神病药物无关，并且有可能为治疗该疾病的所有主要症状群提供疗效。这些计划中最先进的重点是发现抑制甘氨酸转运蛋白 1 (GlyT1) 的新型化合物。甘氨酸是谷氨酸受体 A/-甲基-D-天冬氨酸 (NMDA) 亚型的谷氨酸共激动剂，为增强 NMDA 受体功能同时维持 NMDA 受体激活的活性依赖性提供了一种极好的方法。大量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。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，在动物模型中具有强大的功效，并且没有明显的毒性。第二个项目的重点是发现和优化 M1 毒蕈碱乙酰胆碱受体的高选择性变构激动剂。我们建立了一种新方法，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，并证明这些化合物在动物模型中具有强大的功效，可预测精神分裂症的治疗效果。 Ml 和 GlyTI 项目均基于动物模型的强有力验证和令人兴奋的临床数据，为追求这些新目标提供支持。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药物。我们将从 GlyTI 抑制剂的先导化合物优化开始，然后是 hit-tc-先导化合物和 M1 变构激动剂的先导化合物优化，目标是将与其中每一种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，我们还有一系列其他靶标，我们拥有经过化学多样性验证的命中和早期药物先导化合物，准备进行全面的先导化合物优化工作。虽然没有特别包含在该应用程序中，但这提供了一个强大的发现管道，对于该计划的未来方向非常重要。