Development of an M1 PAM experimental therapeutic for schizophrenia

开发治疗精神分裂症的 M1 PAM 实验疗法

• 批准号: 9140071
• 负责人: P Jeffrey Conn
• 金额: $ 182.77万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140071
• 关键词: Adverse effects; Anhedonia; Animal Model; Animals; Architecture; Attention; Behavioral; Biological Markers; Brain Diseases; Chemistry; Clinical; Clinical Research; Cognitive; Data; Delusions; Development; Disease; Dose; Dose-Limiting; Drug Discovery Groups; Electroencephalography; Equilibrium; Evaluation; Funding; Future; Goals; Grant; Guidelines; Hallucinations; Human; Human Volunteers; Impaired cognition; Investigational Drugs; Investigational New Drug Application; Investigational Therapies; Learning; Mediating; Mental disorders; Muscarinic Acetylcholine Receptor; National Institute of Mental Health; Nervous System Physiology; Neuraxis; Paranoia; Patients; Pharmacologic Substance; Phase; Plasma; Property; Rodent; Safety; Schizophrenia; Sleep; Speech; Strategic Planning; Symptoms; Testing; Therapeutic Agents; Toxicokinetics; Withdrawal; associated symptom; clinical biomarkers; cognitive function; cognitive performance; drug candidate; executive function; improved; long term memory; new therapeutic target; nonhuman primate; novel; novel strategies; novel therapeutics; positive allosteric modulator; pre-clinical; preclinical study; programs; public health relevance; research clinical testing; response; safety study; scale up; social; standard of care; symptom cluster; tool; treatment strategy

 DESCRIPTION (provided by applicant): Available treatments for schizophrenia are not effective in treatment of all major symptoms associated with the disease and induce 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. During the initial funding period of the Vanderbilt NCDDG for discovery of novel treatments for schizophrenia, we made tremendous progress in discovery of drug candidates for novel targets and partnering with pharmaceutical companies to advance these agents to clinical development. In addition, we built on previous clinical studies suggesting that selective activators of the M1 muscarinic acetylcholine receptor have potential for treatment of cognitive disturbances and negative symptoms associated with schizophrenia. We optimized novel highly selective M1 positive allosteric modulators (PAMs) and have extensively evaluated these compounds in animal models of cognitive function and in pre-GLP safety studies. We have identified VU0467319 as a highly optimized M1 PAM that possesses an excellent balance of properties required for selection as a clinical development candidate. We now propose continued support of the Vanderbilt NCDDG to advance VU0467319 into first in human studies and to rigorously establish the doses required to achieve activation of M1 in healthy human volunteers. Project 1 will develop and validate a new translational biomarker for M1 PAM activity that can be used as a surrogate for target engagement and dose-finding studies in early clinical development. Project 2 will provide scale-up synthesis of VU0467319 and other compounds and provide backup clinical candidates to respond to findings with VU0467319 during GLP safety assessment. Project 3 will focus on IND-enabling studies to open an IND to allow clinical evaluation of VU0467319. In Project 4, we will perform safety assessments of VU0467319 in healthy human volunteers and employ the biomarker developed in project 1 to establish the doses required to achieve adequate CNS activity in humans. In addition, project 4 will provide a preliminary assessment of effects of VU0467319 on cognitive function in humans. These studies will provide a fully validated clinical research tool for future clinical studies to fully evaluate the efficacy of a highly optimized M1 PAM in schizophrenia patients.

 描述（由适用提供）：精神分裂症的可用治疗方法无效治疗与该疾病相关的所有主要症状并诱导许多剂量限制的不良反应。这是迫切需要开发新型治疗剂来治疗具有更广泛有效性和更少不良影响的精神分裂症。在范德比尔特NCDG的最初资助期间，我们在发现精神分裂症的新型治疗方法中，在发现候选药物的新目标方面取得了巨大进展，并与制药公司合作，将这些代理商推向临床发展。此外，我们基于先前的临床研究，表明M1毒蕈碱乙酰胆碱受体的选择性激活剂具有治疗认知障碍和与精神分裂症相关的负面症状的潜力。我们优化了新型高度选择性M1阳性变构调节剂（PAM），并在认知功能的动物模型和GLP前安全研究中广泛评估了这些化合物。我们已经将VU0467319确定为高度优化的M1 PAM，它具有选择作为临床开发候选者所需的属性平衡。现在，我们建议vanderbilt NCDG的持续支持将VU0467319推向人类研究的第一名，并严格确定在健康的人类志愿者中激活M1所需的剂量。项目1将开发并验证一种新的翻译生物标志物，用于M1 PAM活动，该标志物可用作早期临床开发中目标参与和剂量调查研究的代理。项目2将提供VU0467319和其他化合物的扩大合成，并提供备用临床候选者，以在GLP安全评估期间对VU0467319的发现做出响应。项目3将着重于辅助研究，以开放IND，以允许对VU0467319的临床评估。在项目4中，我们将对健康的人类志愿者进行VU0467319的安全评估，并采用项目1中开发的生物标志物来确定在人类中实现足够的中枢神经系统活动所需的剂量。此外，项目4将对VU0467319对人类认知功能的影响进行初步评估。这些研究将为未来的临床研究提供全面验证的临床研究工具，以充分评估高度优化的M1 PAM在精神分裂症患者中的有效性。