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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，该抑制剂可以导致未来用于治疗的研究性新药 (IND) 的监管备案阿尔茨海默病（AD）。开发一种可以阻止疾病进展的药物至关重要重要性，因为目前尚无神经保护、阻止疾病进展或提供认知益处。我们的团队从遗传学角度展示了针对 JNK3 的基本原理，其中， FAD 小鼠中 Jnk3 的缺失导致 Ab42 水平和总体斑块负荷显着降低随着神经元数量的增加和认知能力的提高。此外，我们的团队还开发了有效的脑渗透性小分子 JNK3 探针抑制剂，具有良好的 DMPK 特性。然而，这需要优化一类化合物的口服生物利用度。为了实现这一目标，我们将采用药物发现的经典制药方法。我们组建了临床前药物团队涵盖所有方法论（医学化学、生物化学、细胞生物学、神经生物学、体内和离体药理学、配方、该项目将使用 DMPK 和毒理学）。我们将采用迭代复合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、口服给药有利的药代动力学特性以及良好的细胞活性安全概况。我们生成的化合物结构新颖，设计创新，并且性能良好与任何类别的已知 JNK 抑制剂不同，特别是异构体选择性抑制剂。这研究计划旨在通过支持来最大限度地提高临床前成功的机会来自多个类别的化合物，以降低开发单一候选者的风险。来测试我们的假设新结构类别的有效、异构体选择性 JNK3 抑制剂具有低毒性，良好的 DMPK 特性，以及降低抗体水平、改善突触功能的体内功效，并能够提高认知能力，我们提出以下目标：目标 1：发展和提高认知能力优化 JNK3 同工型选择性抑制剂，这些抑制剂具有有效、选择性且具有良好的 DMPK 提供良好的大脑暴露的特性。这一目标将通过利用药物来实现由生化和细胞分析支持的化学。目标 2：测试 JNK 抑制剂的作用包括 5XFAD 和 Tg2576 小鼠在内的两个实验模型证明了体内功效。在此外，我们将证明与人类CYP450缺乏相互作用并测试3-5铅的安全性在大鼠毒性模型中开发化合物。

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.