Development of an M1 PAM experimental therapeutic for schizophrenia
Development of an M1 PAM experimental therapeutic for schizophrenia
批准号:
9140071
负责人:
P Jeffrey Conn
金额:
$182.77万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-09-10 至 2018-06-30
关键词:
Adverse effectsAnhedoniaAnimal ModelAnimalsArchitectureAttentionBehavioralBiological MarkersBrain DiseasesChemistryClinicalClinical ResearchCognitiveDataDelusionsDevelopmentDiseaseDoseDose-LimitingDrug Discovery GroupsElectroencephalographyEquilibriumEvaluationFundingFutureGoalsGrantGuidelinesHallucinationsHumanHuman VolunteersImpaired cognitionInvestigational DrugsInvestigational New Drug ApplicationInvestigational TherapiesLearningMediatingMental disordersMuscarinic Acetylcholine ReceptorNational Institute of Mental HealthNervous System PhysiologyNeuraxisParanoiaPatientsPharmacologic SubstancePhasePlasmaPropertyRodentSafetySchizophreniaSleepSpeechStrategic PlanningSymptomsTestingTherapeutic AgentsToxicokineticsWithdrawalassociated symptomclinical biomarkerscognitive functioncognitive performancedrug candidateexecutive functionimprovedlong term memorynew therapeutic targetnonhuman primatenovelnovel strategiesnovel therapeuticspositive allosteric modulatorpre-clinicalpreclinical studyprogramspublic health relevanceresearch clinical testingresponsesafety studyscale upsocialstandard of caresymptom clustertooltreatment strategy
中文摘要
描述(由申请人提供):精神分裂症的现有治疗方法不能有效治疗与该疾病相关的所有主要症状,并且会引起许多剂量限制性副作用。因此,迫切需要开发具有更广泛功效和更少副作用的新型治疗剂来治疗精神分裂症。在范德比尔特 NCDDG 发现精神分裂症新疗法的初始资助期间,我们在发现新靶标候选药物以及与制药公司合作将这些药物推进临床开发方面取得了巨大进展。此外,我们基于之前的临床研究表明,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阴性症状的潜力。我们优化了新型高选择性 M1 正变构调节剂 (PAM),并在认知功能动物模型和 GLP 前安全性研究中广泛评估了这些化合物。我们已将 VU0467319 确定为高度优化的 M1 PAM,其具有选为临床开发候选药物所需的出色平衡特性。现在,我们建议范德比尔特大学 NCDDG 继续支持,将 VU0467319 推进到人体研究中,并严格确定在健康人类志愿者中实现 M1 激活所需的剂量。项目 1 将开发并验证 M1 PAM 活性的新转化生物标志物,可用作早期临床开发中靶标参与和剂量探索研究的替代品。项目 2 将提供 VU0467319 和其他化合物的放大合成,并提供备用临床候选药物,以应对 GLP 安全评估期间 VU0467319 的发现。项目 3 将重点关注 IND 启用研究,以开放 IND 以便对 VU0467319 进行临床评估。在项目 4 中,我们将在健康人类志愿者中进行 VU0467319 的安全性评估,并利用项目 1 中开发的生物标志物来确定在人体中实现足够的 CNS 活性所需的剂量。此外,项目4将提供VU0467319对人类认知功能影响的初步评估。这些研究将为未来的临床研究提供经过充分验证的临床研究工具,以全面评估高度优化的 M1 PAM 对精神分裂症患者的疗效。
英文摘要
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.
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会议论文
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批准号:8603872
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负责人:P Jeffrey Conn
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依托单位:
Postdoctoral Training in CNS Drug Discovery Research
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批准号:8479436
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资助金额:$23.49万
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财政年份:2011
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负责人:P Jeffrey Conn
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依托单位:
Postdoctoral Training in CNS Drug Discovery Research
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批准号:8296276
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资助金额:$23.6万
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财政年份:2011
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依托单位:
Postdoctoral Training in CNS Drug Discovery Research
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批准号:8661292
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资助金额:$22.2万
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财政年份:2011
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依托单位:
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资助金额:$11.78万
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依托单位:
Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia
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批准号:8605222
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资助金额:$188.05万
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依托单位:
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Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia
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Administrative Core
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