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

摘要 阿尔茨海默病和相关痴呆症(AD/ADRD)具有重大的社会影响，但没有 疾病改良干预措施。先前临床试验失败的根本原因为计划提供指导 重振AD/ADRD治疗的发现和开发进程。具体地说，多元化投资组合 基于临床观察、遗传关联、 病理结果和生化机制。然而，许多项目在资金和资金方面被忽视。 技术追求。先前强调以病理为基础的途径可以通过保留一种治疗性的 强调病理生理学进展机制的离散但互补的方面。突触 功能障碍是一个具有不同潜在目标的例子。突触功能障碍是轻微遗忘症的基础 在经典的组织病理学特征发展之前发生的变化。变性突触 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、多巴胺和5-羟色胺能系统。5-羟色胺能系统既是一种未被探索的 治疗机制，特别是考虑到5-羟色胺不仅仅是一种神经递质。 此外，临床发现AD患者5-羟色胺受体2b(5-HT2bR)的表达增加 大脑和AD患者对非选择性5-HT2bR拮抗剂的反应表明 优化5-HT2bR拮抗剂治疗AD。我们开发了一种小分子，MW01-8-071HAB(=MW071)， 抑制淀粉样β蛋白(Aβ)和tau模型的长时程增强缺陷以及联想记忆和空间记忆 立面。158个已知GPCRs的靶外激动剂和拮抗剂活性的功能筛选 证明MW071是一种选择性的5-HT2bR拮抗剂。重要的是，MW071缺乏5-HT2BR激动剂 活动。避免激动剂活动是具有里程碑意义的。已批准的具有5-HT2bR激动剂活性的药物对 心脏瓣膜毒性，导致停药或黑盒警告。因此，治疗阿尔茨海默病有希望的疗效 相关模型，包括高度选择性拮抗剂活性的药理学概况 激动剂活性，以及备用候选者(MW109)的可用性增加了MW071作为一种 起点。我们拟议的早期研究将进一步降低MW071和MW109的风险，以便产生 并为未来启用IND的后期U01应用程序确定候选人资格： 目标1.根据FDA的指导进行二次药理学分析，作为必要的前奏和坚实的基础 为未来的GxP IND提供临床前安全性和毒理学研究的基础。 目的：验证MW071和MW109对突触和记忆的预防/逆转作用 AD相关动物模型中的损伤。 量化里程碑将决定通过通过/不通过决策点的进展。成功的结果 可交付成果将允许未来支持GxP Ind-Enabling评估和第一个人的评估。

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.