Preclinical development of a novel small molecule inhibitor of Alzheimer's disease-related cognitive impairment

阿尔茨海默病相关认知障碍的新型小分子抑制剂的临床前开发

基本信息

批准号：
10765513
负责人：
OTTAVIO ARANCIO
金额：
$ 32.9万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10765513
关键词：
Agonist Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Animal Model Biochemical Brain Clinical Clinical Trials Defect Deterioration Development Disease Disease Progression Evaluation Failure Foundations Functional disorder Funding Future G-Protein-Coupled Receptors Goals Heart Valves Impaired cognition Instruction Intervention Memory impairment Modeling Neurotransmitters Outcome Pathology Pathway interactions Pharmaceutical Preparations Pharmacology Prevention Process Qualifying Research Risk Serotonergic System Serotonin Serotonin Receptor 5-HT2B Synapses System Therapeutic Toxic effect Toxicology Withdrawal antagonist cholinergic clinical trial readiness efficacy validation first-in-human genetic association high risk neglect noradrenergic novel pharmacologic preclinical development preclinical safety small molecule small molecule inhibitor small molecule therapeutics spatial memory tau Proteins therapeutic candidate therapeutic target

项目摘要

ABSTRACT Alzheimer's disease and related dementias (AD/ADRD) have a significant societal impact, yet there are no disease modifying interventions. Root causes of prior clinical trial failures provide instruction for plans to reinvigorate the AD/ADRD therapeutic discovery and development process. Specifically, a diversified portfolio of candidate therapeutic approaches is available based on clinical observations, genetic associations, pathology outcomes and biochemical mechanisms. However, many are neglected in terms of funding and technical pursuit. The prior emphasis on a pathology-based pathway can be avoided by retaining a therapeutic emphasis on discrete but complementary aspects of pathophysiology progression mechanisms. Synaptic dysfunction is one example with diverse potential targets. Synaptic dysfunction underlies subtle amnesic changes occurring prior to the development of the classical histopathologic hallmarks. Deteriorated synaptic strengthening is associated with remodeling of various neurotransmitter systems, including cholinergic, noradrenergic, dopaminergic and serotonergic systems. The serotonergic system is both an underexplored therapeutic mechanism and is especially attractive considering that serotonin is more than a neurotransmitter. Further, clinical findings that 5-hydroxytryptamine receptor 2b (5-HT2bR) expression is increased in AD patient brains and that AD patients respond to a non-selective 5-HT2bR antagonist suggest the potential utility of optimized 5-HT2bR antagonists in AD. We developed a small molecule, MW01-8-071HAB (=MW071), that suppresses LTP defects as well as associative and spatial memory in models of amyloid-beta (Aβ) and tau elevation. Functional screens for off-target agonist and antagonist activity with 158 known GPCRs demonstrated that MW071 is a selective 5-HT2bR antagonist. Importantly, MW071 lacks 5-HT2BR agonist activity. Avoiding agonist activity is landmark. Approved drugs with 5-HT2bR agonist activity have high risk for cardiac valve toxicity, resulting in withdrawal or black box warnings. Therefore, the promising efficacy in AD relevant models, a pharmacological profile that includes highly selective antagonist activity in the absence of agonist activity, and the availability of a back-up candidate (MW109) adds to the overall appeal of MW071 as a starting point. Our proposed early-stage studies will further de-risk MW071 and MW109 in order to generate and qualify a candidate for a future IND-enabling late stage U01 application: Aim 1. Perform secondary pharmacology analyses following FDA guidance, as a necessary prelude and a firm foundation for future GxP IND-enabling preclinical safety and toxicology research. Aim 2. Validate the efficacy of MW071 and MW109 in prevention/reversal of synaptic and memory impairments in AD-relevant animal models. Quantitative milestones will determine progression through Go/No Go decision points. Successful outcomes and deliverables will allow for future support of GxP IND-enabling evaluation and first-in-human assessment.

抽象的阿尔茨海默氏病和相关痴呆症 (AD/ADRD) 具有重大的社会影响，但目前还没有先前临床试验失败的根本原因为治疗计划提供指导。重振 AD/ADRD 治疗发现和开发过程，具体来说，是多元化的产品组合。根据临床观察、遗传关联、然而，许多在资金和生化机制方面被忽视。通过保留治疗方法可以避免先前强调基于病理学的途径。强调病理生理学进展机制的离散但互补的方面。功能障碍是一个例子，突触功能障碍是微妙的遗忘症的基础。在出现典型的组织病理学特征之前发生变化。强化与各种神经递质系统的重塑有关，包括胆碱能、去甲肾上腺素能系统、多巴胺能系统和血清素能系统血清素能系统均尚未得到充分开发。考虑到血清素不仅仅是一种神经递质，它的治疗机制尤其有吸引力。此外，临床发现 AD 患者 5-羟色胺受体 2b (5-HT2bR) 表达增加大脑和 AD 患者对非选择性 5-HT2bR 拮抗剂的反应表明了我们开发了一种小分子 MW01-8-071HAB (=MW071)，用于治疗 AD。抑制β淀粉样蛋白 (Aβ) 和 tau 模型中的 LTP 缺陷以及联想和空间记忆使用 158 个已知 GPCR 进行脱靶激动剂和拮抗剂活性的功能筛选。重要的是，MW071s 5-HT2BR 激动剂避免激动剂活性具有里程碑意义，具有 5-HT2bR 激动剂活性的药物具有较高的风险。心脏瓣膜毒性，导致戒断或黑框警告，因此在 AD 中的疗效很有前景。相关模型，药理学特征，包括在不存在的情况下的高度选择性拮抗剂活性激动剂活性，以及备用候选药物 (MW109) 的可用性增加了 MW071 作为药物的整体吸引力我们提出的早期研究将进一步降低 MW071 和 MW109 的风险，以便产生。并使候选人有资格获得未来支持 IND 的后期 U01 申请：目标 1. 按照 FDA 指导进行二级药理学分析，作为必要的前奏和坚实的基础为未来支持 GxP IND 的临床前安全性和毒理学研究奠定了基础。目标 2. 验证 MW071 和 MW109 在预防/逆转突触和记忆方面的功效 AD 相关动物模型中的损伤。定量里程碑将决定通过/不进行决策点的进展。和可交付成果将允许未来支持 GxP IND 评估和首次人体评估。