Preclinical drug development of isoform selective JNK3 inhibitors for Alzheimer's disease.
治疗阿尔茨海默病的异构体选择性 JNK3 抑制剂的临床前药物开发。
基本信息
- 批准号:9217122
- 负责人:
- 金额:$ 85.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-01 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholineAdverse effectsAlpha CellAlzheimer&aposs DiseaseAmyloid beta-ProteinBackBasic ScienceBiochemicalBiochemistryBiological AssayBiological AvailabilityBody Weight decreasedBrainCachexiaCell LineCellsCellular biologyClinical ResearchClinical assessmentsCognitionCognitiveCoupledDataDefectDevelopmentDisease ProgressionDoseDrug DesignDrug KineticsEnzymesEthersExhibitsExperimental ModelsFormulationFutureGoalsHumanInvestigational DrugsIon ChannelKnock-outLeadMAPK14 geneMAPK8 geneMAPK9 geneMediatingMetabolic ControlMethodologyModelingMusN-terminalNeurobiologyNeuronsOralPathologyPatientsPeptidesPharmaceutical ChemistryPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhosphorylationPhosphotransferasesPreclinical Drug DevelopmentPresenile Alzheimer DementiaProductionPropertyProtein IsoformsRattusResearchRiskSafetySeriesStressStructureStructure-Activity RelationshipTestingTg2576TimeTissuesToxic effectToxicologyTreatment EfficacyV717FWeightbaseclinical efficacycognitive abilitydesigndrug developmentdrug discoverydrug metabolismexperienceimprovedin vivoinhibitor/antagonistinnovationneuronal survivalnovelpre-clinicalpreclinical developmentprogramsreceptorresearch and developmentsafety testingsmall moleculesuccesssynaptic function
项目摘要
The goal of this proposal is to develop a c-jun-N-terminal kinase isoform selective inhibitor that can lead
to a future regulatory filing for an investigational new drug (IND) to be used in the treatment of
Alzheimer's Disease (AD). Development of a drug that can halt disease progression is of paramount
importance as there are no current therapies that are neuroprotective, halt disease progression, or
provide cognitive benefit. The rationale for targeting JNK3 was shown genetically by our team, wherein,
deletion of Jnk3 from FAD mice produced a dramatic reduction in Ab42 levels and overall plaque load
along with increased neuronal number and improved cognition. In addition our team has developed a
potent, brain penetrant small molecule JNK3 probe inhibitor with good DMPK properties. However, this
class of compounds needs to be optimized for oral bioavailability. To accomplish this we will employ a
classical pharmaceutical approach to drug discovery. We have assembled a team with preclinical drug
development and basic research experience that encompasses all of the methodologies (medicinal
chemistry, biochemistry, cell biology, neurobiology, in vivo and ex vivo pharmacology, formulation,
DMPK, and toxicology) that will be utilized in this project. We will employ an iterative compound
optimization approach that will produce a series of compounds from multiple structural classes that
have potent in vivo efficacy, favorable pharmacokinetic properties for oral dosing and a good cellular
safety profile. The compounds we have generated are structurally novel, innovative in design, and well
differentiated from known JNK inhibitors from any class, particularly isoform selective inhibitors. The
research plan is designed to maximize the chance for preclinical success by having back-up
compounds, from multiple classes, to mitigate the risk of developing a single candidate. To test our
hypothesis that novel structural classes of potent, isoform selective JNK3 inhibitors with low toxicity,
favorable DMPK properties, and in vivo efficacy in decreasing Ab levels, improving synaptic function,
and improving cognition can be generated, we propose the following aims: Aim 1: Develop and
optimize JNK3 isoform selective inhibitors that are potent, selective, and have favorable DMPK
properties that provide good brain exposure. This aim will be accomplished by utilizing medicinal
chemistry supported by biochemical and cell-based assays. Aim 2: Test the actions of JNK inhibitors in
two experimental models including 5XFAD and Tg2576 mice to demonstrate in vivo efficacy. In
addition, we will demonstrate lack of interaction with human CYP450s and test the safety of 3-5 lead
development compounds in rat toxicity models.
本提案的目标是开发一种c-jun- n-末端激酶异构体选择性抑制剂,可以导致
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Yangbo Feng其他文献
Yangbo Feng的其他文献
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{{ truncateString('Yangbo Feng', 18)}}的其他基金
Preclinical drug development of isoform selective JNK3 inhibitors for Alzheimer's disease.
治疗阿尔茨海默病的异构体选择性 JNK3 抑制剂的临床前药物开发。
- 批准号:
10132954 - 财政年份:2017
- 资助金额:
$ 85.19万 - 项目类别:
Development of small molecule Limk inhibitors for probing ocular diseases
开发用于探测眼部疾病的小分子 Limk 抑制剂
- 批准号:
8306733 - 财政年份:2011
- 资助金额:
$ 85.19万 - 项目类别:
Development of small molecule Limk inhibitors for probing ocular diseases
开发用于探测眼部疾病的小分子 Limk 抑制剂
- 批准号:
8166343 - 财政年份:2011
- 资助金额:
$ 85.19万 - 项目类别:
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