Novel PDE5 inhibitors as a therapeutic tool against Alzheimer's Disease

新型 PDE5 抑制剂作为阿尔茨海默病的治疗工具

基本信息

批准号：
8225192
负责人：
OTTAVIO ARANCIO
金额：
$ 37.71万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225192
关键词：
AP40 Acute Acute Toxicity Tests Address Adult Affect Affinity Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Diseases Animals Area Attention Biological Assay Biological Availability Biology Blood - brain barrier anatomy Brain Brain region Buffers CREB1 gene Cardiac Cell model Central Nervous System Diseases Characteristics Chronic Clinical Cognition Cognitive Collaborations Contracts Cyclic GMP Cyclic GMP-Dependent Protein Kinases Data Dementia Deposition Disease Drug Compounding Drug Interactions Drug Kinetics Elderly Enzymes Failure Fright Functional disorder Glutamates Goals Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Inhibitory Concentration 50 Laboratories Lead Learning Legal patent Long-Term Potentiation Memory Memory impairment Mus Mutation Neurofibrillary Tangles Nitric Oxide Nitric Oxide Signaling Pathway Pathway interactions Patients Penetration Pharmaceutical Preparations Play Population Positioning Attribute Principal Investigator Property Protein Isoforms Protein Structure Initiative Publishing Rattus Role Safety Senile Plaques Severities Short-Term Memory Slice Solubility Soluble Guanylate Cyclase Specificity Staging Synapses Synaptic Transmission Testing Therapeutic Time Toxic effect Transgenic Mice Viagra Withdrawal Work aged aqueous cognitive function design drug candidate drug market drug synthesis improved in vivo inhibitor/antagonist liver metabolism memory recognition mouse model neurotransmission novel phosphodiesterase V phosphoric diester hydrolase pre-clinical presenilin-1 prevent programs public health relevance quinoline sildenafil success synaptic function tool transcription factor transgenic model of alzheimer disease uptake

项目摘要

DESCRIPTION (provided by applicant): One of the important targets for developing a causal therapy for Alzheimer's disease (AD) is represented by synapses. The nitric oxide signaling pathway is thought to play an important role in the synapse during plasticity and memory. Published data from Dr. Arancio's laboratory have demonstrated the involvement of the pathway in amyloid-beta-induced synaptic dysfunction. Most importantly, sildenafil, an inhibitor of the cGMP-degrading enzyme phosphodiesterase V (PDE5), one of the components of the pathway, ameliorates synaptic and memory abnormalities in an amyloid-depositing mouse model, the APP/PS1 animal. Thus, the overall purpose of this project is to identify molecules that, by enhancing cGMP levels, re-establish normal cognition in the APP/PS1 mouse model. None of the existing PDE5 inhibitors has been developed to counteract diseases of the CNS and at the same time possesses the selectivity required for chronic administration to an elderly population with comorbid conditions such as AD patients. To that end, a new compound has been synthesized in our laboratories that will serve for lead optimization. YF012403 has high potency and excellent selectivity for PDE5 over other PDE isoforms. Moreover, it crosses the blood brain barrier, and has not shown acute toxicity signs. Most importantly, it ameliorates beta-amyloid induced synaptic and memory dysfunction. The following aims will be addressed by combining med/chem expertise with expertise on the biology of AD and mouse models of the disease: a) to design and synthesize novel PDE5 inhibitors which are optimized for AD; b) to identify compounds with high affinity and good selectivity for PDE5; c) to determine whether new PDE5 inhibitors have good pharmacokinetic and are safe; d) to screen the new PDE5 inhibitors by selecting compounds that rescue synaptic dysfunction in APP/PS1 mice; e) to further screen PDE5 inhibitors selected through tests on synaptic function to examine if they prevent cognitive abnormalities in APP/PS1 mice. On the completion of these studies we will identify a new drug for the treatment of cognitive loss in AD. The whole project will be organized in clear milestones with objective success/failure criteria and GO/NO GO decision points. PUBLIC HEALTH RELEVANCE STATEMENT: Currently used therapies against Alzheimer's disease have limited efficacy. We have found that phosphodiesterase 5 inhibitors might counteract memory deficits in animal of the disease. However, none of the existing inhibitors has been developed to counteract CNS diseases. We now propose to find phosphodiesterase 5 inhibitors that might be used in chronic CNS diseases such as Alzheimer's disease.

描述（由申请人提供）：为阿尔茨海默氏病（AD）开发因果疗法的重要目标之一是突触的代表。一氧化氮信号通路被认为在可塑性和记忆过程中在突触中起重要作用。来自Arancio博士实验室的发布数据证明了该途径在淀粉样蛋白β诱导的突触功能障碍中的参与。最重要的是，Sildenafil是CGMP降解酶磷酸二酯酶V（PDE5）的抑制剂，该途径的组成部分之一，可以在淀粉样蛋白抑制的小鼠模型，App/PS1动物的淀粉样蛋白脱位中的突触和记忆异常。因此，该项目的总体目的是确定通过增强CGMP水平的分子，重新建立APP/PS1小鼠模型中的正常认知。现有的PDE5抑制剂尚未开发用于抵消中枢神经系统的疾病，同时还具有长期对患有合并症患者（如AD患者）的老年人群的选择性。为此，在我们的实验室中合成了一种新化合物，该化合物将用于铅优化。与其他PDE同工型相比，YF012403对PDE5具有高效力和出色的选择性。此外，它越过血脑屏障，尚未显示出急性毒性迹象。最重要的是，它可以改善β-淀粉样蛋白诱导的突触和记忆功能障碍。以下目标将通过将MED/CHEM专业知识与AD生物学和疾病的小鼠模型的专业知识相结合：a）设计和合成针对AD优化的新型PDE5抑制剂； b）鉴定具有高亲和力和良好选择性PDE5的化合物； c）确定新的PDE5抑制剂是否具有良好的药代动力学并且是安全的； d）通过选择在App/PS1小鼠中挽救突触功能障碍的化合物来筛选新的PDE5抑制剂； e）进一步筛选通过突触功能测试选择的PDE5抑制剂，以检查它们是否预防APP/PS1小鼠的认知异常。这些研究完成后，我们将确定一种用于治疗AD认知损失的新药。整个项目将以具有客观成功/失败标准的明确里程碑进行组织，并且没有执行决策点。公共卫生相关声明：目前使用针对阿尔茨海默氏病的疗法有限。我们发现磷酸二酯酶5抑制剂可能会抵消该疾病动物的记忆缺陷。但是，没有开发出一种现有的抑制剂来抵消中枢神经系统疾病。现在，我们建议在慢性中枢神经系统疾病（如阿尔茨海默氏病）中找到磷酸二酯酶5抑制剂。