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
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Discovery of mGlu receptor PAMs for treatment of schizophrenia
-
批准号:10531546
-
项目类别:
-
资助金额:$67.81万
-
财政年份:2019
-
负责人:P Jeffrey Conn
-
依托单位:
Discovery of mGlu receptor PAMs for treatment of schizophrenia
-
批准号:10305625
-
项目类别:
-
资助金额:$70.71万
-
财政年份:2019
-
负责人:P Jeffrey Conn
-
依托单位:
Novel mGlu5 negative allosteric modulators as first-in-class non-addictive analgesic therapeutics
-
批准号:10450295
-
项目类别:
-
资助金额:$19.12万
-
财政年份:2019
-
负责人:P Jeffrey Conn
-
依托单位:
Discovery of mGlu receptor PAMs for treatment of schizophrenia
-
批准号:10063834
-
项目类别:
-
资助金额:$71.46万
-
财政年份:2019
-
负责人:P Jeffrey Conn
-
依托单位:
Novel mGlu5 Negative Allosteric Modulators as First-in-Class Non-Addictive Analgesic Therapeutics
-
批准号:10477066
-
项目类别:
-
资助金额:$19.12万
-
财政年份:2019
-
负责人:P Jeffrey Conn
-
依托单位:
Novel mGlu5 negative allosteric modulators as first-in-class non-addictive analgesic therapeutics
-
批准号:10581793
-
项目类别:
-
资助金额:$7.66万
-
财政年份:2019
-
负责人:P Jeffrey Conn
-
依托单位:
Development of mGIuR5 NAMS for Treatment of Major Depression
-
批准号:8434427
-
项目类别:
-
资助金额:$134.01万
-
财政年份:2013
-
负责人:P Jeffrey Conn
-
依托单位:
Development of mGIuR5 NAMS for Treatment of Major Depression
-
批准号:8603872
-
项目类别:
-
资助金额:$120.61万
-
财政年份:2013
-
负责人:P Jeffrey Conn
-
依托单位:
Discovery and Optimization of Selective Negative Allosteric Modulators of mGluR3
-
批准号:8726488
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2012
-
负责人:P Jeffrey Conn
-
依托单位:
Postdoctoral Training in CNS Drug Discovery Research
-
批准号:8479436
-
项目类别:
-
资助金额:$23.49万
-
财政年份:2011
-
负责人:P Jeffrey Conn
-
依托单位:
Postdoctoral Training in CNS Drug Discovery Research
-
批准号:8296276
-
项目类别:
-
资助金额:$23.6万
-
财政年份:2011
-
负责人:P Jeffrey Conn
-
依托单位:
Postdoctoral Training in CNS Drug Discovery Research
-
批准号:8661292
-
项目类别:
-
资助金额:$22.2万
-
财政年份:2011
-
负责人:P Jeffrey Conn
-
依托单位:
Postdoctoral Training in CNS Drug Discovery Research
-
批准号:8078638
-
项目类别:
-
资助金额:$11.78万
-
财政年份:2011
-
负责人:P Jeffrey Conn
-
依托单位:
Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia
-
批准号:8605222
-
项目类别:
-
资助金额:$188.05万
-
财政年份:2010
-
负责人:P Jeffrey Conn
-
依托单位:
Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia
-
批准号:8423776
-
项目类别:
-
资助金额:$180.53万
-
财政年份:2010
-
负责人:P Jeffrey Conn
-
依托单位:
Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia
-
批准号:7778028
-
项目类别:
-
资助金额:$189.15万
-
财政年份:2010
-
负责人:P Jeffrey Conn
-
依托单位:
Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia
-
批准号:8029598
-
项目类别:
-
资助金额:$187.45万
-
财政年份:2010
-
负责人:P Jeffrey Conn
-
依托单位:
Vanderbilt NCDDDG for Discovery of Novel Treatments for Schizophrenia
-
批准号:8231498
-
项目类别:
-
资助金额:$188.05万
-
财政年份:2010
-
负责人:P Jeffrey Conn
-
依托单位:
Administrative Core
-
批准号:7988515
-
项目类别:
-
资助金额:$15.93万
-
财政年份:2010
-
负责人:P Jeffrey Conn
-
依托单位:
Recruitment of in Vivo Neuropharmacologist to Support CNS Drug Discovery Research
-
批准号:7856434
-
项目类别:
-
资助金额:$70.35万
-
财政年份:2009
-
负责人:P Jeffrey Conn
-
依托单位:
海外基金