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）具有显著的社会影响，但目前还没有 改善疾病的干预措施。既往临床试验失败的根本原因为计划提供了指导， 重振AD/ADRD治疗发现和开发进程。具体来说，就是多元化的投资组合 基于临床观察，遗传关联， 病理结果和生化机制。然而，许多项目在资金方面被忽视， 技术追求。通过保留一种治疗方法，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。突触 功能障碍是具有多种潜在靶点的一个例子。突触功能障碍是轻微遗忘症的基础 在经典组织病理学标志出现之前发生的变化。退化突触 强化与各种神经递质系统，包括胆碱能， 去甲肾上腺素能、多巴胺能和肾上腺素能系统。电子能系统是一个未被充分研究的 考虑到5-羟色胺不仅仅是一种神经递质， 此外，临床发现5-羟色胺受体2b（5-HT 2bR）表达在AD患者中增加， 大脑和AD患者对非选择性5-HT 2bR拮抗剂的反应表明， 优化的5-HT 2bR拮抗剂在AD中的作用。我们开发了一种小分子，MW 01 -8- 071 HAB（= MW 071）， 抑制淀粉样蛋白β（Aβ）和tau模型中的LTP缺陷以及联想和空间记忆 提升使用158种已知GPCR对脱靶激动剂和拮抗剂活性进行功能筛选 MW 071是一种选择性5-HT 2bR拮抗剂。重要的是，MW 071缺乏5-HT 2BR激动剂 活动避免激动剂活性是里程碑式的。具有5-HT 2bR激动剂活性的批准药物具有高风险， 心脏瓣膜毒性，导致退出或黑框警告。因此，在AD中有希望的疗效 相关模型，药理学特征，包括在不存在 激动剂活性，以及备用候选药物（MW 109）的可用性增加了MW 071作为 起点我们建议的早期研究将进一步降低MW 071和MW 109的风险， 并使候选人有资格获得未来的IND启用后期U 01申请： 目标1.按照FDA指南进行次要药理学分析，作为必要的前奏和确定 为未来的GxP IND临床前安全性和毒理学研究奠定基础。 目标二。研究MW 071和MW 109在预防/逆转突触和记忆障碍中的功效。 AD相关动物模型中的损伤。 量化里程碑将通过Go/No Go决策点确定进展。成功结果 和交付物将允许未来支持GxP IND使能评价和首次人体评估。

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.