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):现有的精神分裂症治疗方法不能有效地治疗与疾病相关的所有主要症状,并导致一些剂量限制的不良反应。因此,迫切需要开发新的治疗药物来治疗精神分裂症,具有更广泛的疗效和更少的不良反应。在Vanderbilt NCDDG发现精神分裂症新疗法的最初资助期内,我们在发现新靶点的候选药物以及与制药公司合作将这些药物推向临床开发方面取得了巨大进展。此外,我们建立在以前的临床研究的基础上,该研究表明M1乙酰胆碱受体的选择性激活剂具有治疗与精神分裂症相关的认知障碍和阴性症状的潜力。我们优化了新的高选择性M1正变构调节剂(PAM),并在认知功能的动物模型和GLP前安全性研究中广泛评估了这些化合物。我们已经确定VU0467319是一种高度优化的M1 PAM,具有选择作为临床开发候选药物所需的良好性能平衡。我们现在建议继续支持Vanderbilt NCDDG将VU0467319推进到人类研究的第一位,并严格确定在健康人体志愿者中实现M1激活所需的剂量。项目1将开发和验证一种新的M1 PAM活性的翻译生物标记物,该标记物可用作早期临床开发中靶点参与和剂量发现研究的替代。项目2将提供VU0467319和其他化合物的放大合成,并提供后备临床候选药物,以应对GLP安全性评估期间VU0467319的发现。项目3将重点放在启用IND的研究上,以打开IND以允许对VU0467319进行临床评估。在项目4中,我们将在健康的人类志愿者身上进行VU0467319的安全性评估,并使用项目1中开发的生物标记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一个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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依托单位:
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批准号:8479436
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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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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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