Drug discovery of COMT inhibitors to treat cognitive deficits in schizophrenia

 描述（由申请人提供）：精神分裂症是一种破坏性的神经发育障碍，影响约1%的人口。虽然氟哌啶醇、氯氮平和奥氮平等抗精神病药物的出现改善了患有这种疾病的人的生活，但这些药物并不是对所有症状领域都有效，并且它们具有一系列严重的副作用，包括心血管、代谢、免疫学和神经学作用。因此，迫切需要新的治疗选择，特别是针对阴性和认知症状领域的治疗。最近的遗传学和药理学研究表明，儿茶酚-O-甲基转移酶（COMT）在调节前额叶皮质多巴胺水平中起着重要作用，这对精神分裂症患者认知受损的几个方面很重要。在临床前和临床研究中，COMT抑制剂已被证明可改善工作记忆;然而，目前临床上可用的COMT抑制剂存在药代动力学差、脑渗透不足和肝毒性的问题。基于已经确定新的COMT抑制剂先导物的初步研究，我们建议设计在效力、选择性、脑渗透和药代动力学方面优化的新型COMT抑制剂。我们提出了一个全面的研究计划，将设计，合成和测试新的COMT抑制剂的效力，选择性，脑渗透和药代动力学的基础上，我们的新线索（具体目标1和3）。结构生物学和建模研究将更好地定义COMT（特定目的2）的膜结合和可溶形式之间的差异，并有助于设计新的抑制剂。将在啮齿动物行为模型中评价先导化合物，以评估认知改善以及评价混杂副作用（具体目标4）。药物发现的迭代周期将导致鉴定出一种化合物，该化合物不仅可以在体内认知模型的背景下探索COMT抑制的作用，而且还可以成为临床开发的候选物。该项目最终旨在发现一种新的治疗方法，用于治疗许多精神分裂症患者中出现的衰弱性认知障碍，目前还没有有效的选择。这里确定的化合物不仅使我们能够探索COMT抑制在体内认知模型中的作用，而且还可以作为临床前评价的候选药物，作为精神分裂症认知障碍的新型治疗方法。

 DESCRIPTION (provided by applicant): Schizophrenia is a devastating neurodevelopmental disorder affecting approximately 1% of the population. While the emergence of antipsychotics such as haloperidol, clozapine, and olanzapine has improved the lives of people suffering from this disease, these drugs are not effective on all symptom domains, and they have a range of serious side effects, including cardiovascular, metabolic, immunological, and neurologic effects. Therefore, new treatment options, particularly therapeutics targeting the negative and cognitive symptom domains, are desperately needed. Recent genetic and pharmacological studies have demonstrated that catechol-O-methyl transferase (COMT) plays a significant role in regulating prefrontal cortical dopamine levels, which are important for several aspects of cognition that are impaired in schizophrenia. COMT inhibition has been shown to improve working memory in preclinical and clinical studies; however, the current clinically available COMT inhibitors suffer from poor pharmacokinetics, inadequate brain penetration, and liver toxicity. Based on preliminary studies that have identified new COMT inhibitor leads, we propose to design novel COMT inhibitors that are optimized in terms of potency, selectivity, brain penetration, and pharmacokinetics. We propose a comprehensive research program that will design, synthesize and test new COMT inhibitors for potency, selectivity, brain penetration, and pharmacokinetics based on our new leads (Specific Aims 1 and 3). Structural biology and modeling studies will better define differences between the membrane-bound and soluble forms of COMT (Specific Aim 2) and contribute to design of new inhibitors. Leading compounds will be evaluated in rodent models of behavior to assess improvements in cognition as well as to evaluate confounding side effects (Specific Aim 4). The iterative cycle of drug discovery will lead to identification of a compound that can not only explore the role of COMT inhibition in the context of in vivo cognition models, but also be a candidate for clinical development. This project is ultimately directed toward the discovery of a novel treatment for the debilitating cognitive impairment seen in many patients with schizophrenia, for which there are currently no effective options. The compounds identified here will not only allow us to explore the role of COMT inhibition in the context of in vivo cognition models but also serve as drug candidates for preclinical evaluation as novel treatments for cognitive impairment in schizophrenia.