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：
10132954
负责人：
Yangbo Feng
金额：
$ 83.71万
依托单位：
OHIO STATE UNIVERSITY
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132954
关键词：
Acetylcholine Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid beta-42 Amyloid beta-Protein Back Basic Science Biochemical Biochemistry Biological Assay Biological Availability Body Weight decreased Brain Cachexia Cell Line Cells Cellular biology Clinical Research Clinical assessments Cognition Coupled Data Defect Development Disease Progression Dose Drug Design Drug Kinetics Enzymes Ethers Exhibits Experimental Models Formulation Future Goals Human Investigational Drugs Ion Channel Knock-out Lead MAPK8 gene MAPK9 gene Mediating Metabolic Control Methodology Modeling Mus N-terminal Neurobiology Neurons Oral Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phosphorylation Phosphotransferases Preclinical Drug Development Presenile Alzheimer Dementia Production Property Protein Isoforms Rattus Research Risk Safety Series Structure Structure-Activity Relationship Testing Tg2576 Time Tissues Toxic effect Toxicology V717F Weight base clinical efficacy cognitive ability cognitive benefits design drug development drug discovery drug metabolism endoplasmic reticulum stress experience improved in vivo inhibitor/antagonist innovation neuronal survival novel p38 Mitogen Activated Protein Kinase pre-clinical preclinical development programs receptor research and development safety testing side effect small molecule success synaptic function therapeutically effective

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.

该建议的目的是开发一个可以领导的C-Jun-N-末端激酶同工型选择性抑制剂向未来的调查新药（IND）进行监管申请阿尔茨海默氏病（AD）。能够停止疾病进展的药物的开发至关重要重要性是因为目前没有神经保护性，停止疾病进展或提供认知益处。我们的团队在遗传上显示了针对JNK3的基本原理，其中从FAD小鼠中删除JNK3会导致AB42水平和整体斑块负载显着降低随着神经元数量增加和认知的改善。此外，我们的团队已经开发了具有良好DMPK特性的有效的，有效的大脑渗透小分子JNK3探针抑制剂。但是，这个对于口服生物利用度，需要优化一类化合物。为了实现这一目标，我们将采用药物发现的经典药物方法。我们已经组建了一个临床前药的团队开发和基础研究经验包括所有方法（药用化学，生物化学，细胞生物学，神经生物学，体内和体外药理学，配方， DMPK和毒理学）将在该项目中使用。我们将采用迭代化合物优化方法将产生来自多个结构类别的一系列化合物具有有效的体内功效，口服剂量的有利的药代动力学特性和良好的细胞安全概况。我们生成的化合物是结构上新颖的，设计创新的，井与已知的JNK抑制剂不同，尤其是同工型选择性抑制剂。这研究计划旨在通过备份来最大化临床前成功的机会从多个类别来减轻发展单个候选者的风险。测试我们的假设具有低毒性的新型结构类别的同工型选择性JNK3抑制剂，有利的DMPK特性和在降低AB水平的体内功效，改善突触功能，并且可以产生改善认知，我们提出以下目的：目标1：开发和优化有效，选择性且具有良好DMPK的JNK3同工型选择性抑制剂提供良好大脑暴露的特性。这个目标将通过使用药用来实现化学由生化和基于细胞的测定支持。目标2：测试JNK抑制剂在两个实验模型，包括5XFAD和TG2576小鼠，以证明体内功效。在此外，我们将证明与人CYP450的相互作用不足，并测试3-5铅的安全性大鼠毒性模型中的开发化合物。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

APP upregulation contributes to retinal ganglion cell degeneration via JNK3.

DOI：
10.1038/s41418-017-0005-3
发表时间：
2018-03
期刊：
Cell death and differentiation
影响因子：
12.4
作者：
Liu C;Zhang CW;Zhou Y;Wong WQ;Lee LC;Ong WY;Yoon SO;Hong W;Fu XY;Soong TW;Koo EH;Stanton LW;Lim KL;Xiao ZC;Dawe GS
通讯作者：
Dawe GS

Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors.