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Development of patented tricyclic pyrones molecules for the treatment of Alzheimer’s Disease

开发用于治疗阿尔茨海默病的专利三环吡喃酮分子

基本信息

批准号：
9442675
负责人：
Xinmin Simon Xie
金额：
$ 96.07万
依托单位：
AFASCI, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2021-02-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9442675
关键词：
APP-PS1 Adverse effects Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyloid beta-Protein Binding Proteins Biological Assay Biological Availability Blood - brain barrier anatomy Brain Brain Diseases Brain imaging Calcium California Chronic Clinical Cognition Collaborations Contract Services Cytochrome P450 Cytoprotection Dementia Deposition Development Disease Drug Kinetics Early treatment Elderly Electrophysiology (science)Event Excitatory Postsynaptic Potentials Excretory function Exhibits Functional disorder Galantamine Goals Grant Health Hepatocyte Hippocampus (Brain)Homeostasis Human Image Impairment Inflammation Investigation Investigational Drugs Investigational New Drug Application Joints Kansas Lead Learning Legal patent Link Long-Term Potentiation Longitudinal Studies Mediating Medical Memantine Memory Memory impairment Metabolism Methods Modeling Molecular Motor Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Degeneration Neurodegenerative Disorders Oral Oral Administration Outcome Pathologic Pathology Penetration Permeability Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Plasma Population Preparation Preventive Provider Pyrones Rattus Rodent Safety Site Slice Small Business Innovation Research Grant Symptoms Synapses Techniques Testing Therapeutic Toxic effect Toxicology Transgenic Mice Transgenic Organisms Universities abeta oligomer abeta toxicity base behavior test behavioral impairment brain tissue clinical development design donepezil drug candidate drug development drug metabolism excitotoxicity extracellular hyperphosphorylated tau in vivo insight intraneuronal beta amyloid mouse model neuron loss neuroprotection neurotransmission novel novel therapeutics phase 1 study programs protein biomarkers receptor function rivastigmine service organization success targeted treatment tau Proteins tau-1 therapeutic candidate therapy design trafficking treatment trial

项目摘要

7. Project Summary/Abstract Alzheimer’s disease (AD) afflicts approximately 44 million people worldwide and is the most common cause of dementia in the elderly. There is an unmet medical need for the development of new Alzheimer’s disease therapeutics. Amyloid-β (Aβ) deposited in the Alzheimer’s diseased brain has been hypothesized to initiate a cascade of molecular changes leading to synaptic dysfunction, inflammation, and neuronal death. Therefore, designing therapies targeting Aβ and downstream events have become major strategies in Alzheimer’s disease drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone compounds (TPs) that show potent cell protection against Aβ toxicity. In our completed SBIR Phase I project, the lead compounds CP2 and TP70 were found to have high oral bioavailability, excellent blood–brain barrier permeability, and low toxicity. Administering compounds orally to young Alzheimer’s disease transgenic mouse models in a “preventive trial” resulted in substantially reduced soluble and insoluble Aβ species in the brain and preserved memory and motor function. Furthermore, we have found that the lead TPs decreased both intraneuronal and extracellular Aβ aggregates as well as hyperphosphorylated tau (p-tau), restored axonal trafficking, and modulated hippocampal synaptic NMDA-mediated activity and plasticity — these multiple synergistic cellular actions, rather than anti-Aβ toxicity alone, could be potential mechanisms underlying their in vivo effects. In this proposed SBIR Phase II project, our original Phase I investigative team with additional expertise in rodent brain imaging, clinical Alzheimer’s disease treatments, and non-GLP toxicity study providers, will conduct longitudinal studies of pharmacokinetics and pharmacodynamics (PK/PD) on the two aforementioned TP molecules in a new transgenic rat model of Alzheimer’s disease, in order to select the best lead as the IND candidate. We now choose the new TgF344-AD rat model for our studies because they exhibit accumulation of oligomeric Aβ, Aβplaque formation, Tau pathology, behavioral Impairment, and neuronal loss that faithfully recapitulate hallmarks of human Alzheimer’s disease. We will achieve our goal by accomplishing the following Specific Aims: 1. Conduct PK/PD studies of CP2 and TP70 on TgF344-AD rats using our established assays/tests. The drug metabolism and PK studies include plasma and hepatocyte stability, plasma and brain protein binding, plasma and CSF concentrations, metabolite identification, P450 inhibition/induction, and excretion. In vivo efficacy especially cognition, brain imaging, and pathologic outcomes will be examined along with Aβ and tau protein biomarkers in CSF and brain to correlate with PD outcomes. 2. Preparation for IND-enabling studies. Conduct pilot safety pharmacology and non-GLP toxicology on the selected therapeutic candidates through contract service organizations to help make a go/no-go decision for IND-enabling studies in a Competing Renewal of SBIR Phase IIB or other programs. 3. Explore mechanisms of action underlying CP2 and TP70 efficacy in the transgenic rat model of Alzheimer disease. We will investigate CP2 and TP70 modulation of hippocampal synaptic, particularly NMDA receptor-mediated synaptic activity, plasticity and extrasynaptic NMDA receptors-mediated activity, and explore their links to other molecular and cellular actions Success in Phase II will lead to an IND candidate. Once an IND application is filed, it will attract non-government support and pharmaceutical partners for clinical development of this novel drug candidate for the treatment of Alzheimer’s disease.

7. 项目总结/文摘