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

• 批准号: 10608172
• 负责人: OTTAVIO ARANCIO
• 金额: $ 144.48万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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/10608172
• 关键词: Address; Agonist; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Behavior; Biochemical; Brain; Clinical; Clinical Trials; Clinical assessments; Data; Defect; Deterioration; Development; Disease; Disease Progression; Evaluation; Failure; Foundations; Functional disorder; Funding; Future; G-Protein-Coupled Receptors; Genetic; Goals; Health; Heart Valves; Home; Impaired cognition; Instruction; Intervention; Investigation; Knowledge; Life Experience; Lisuride; Long-Term Potentiation; Measures; Memory impairment; Modeling; Neurofibrillary Tangles; Neurotransmitters; Onset of illness; Outcome; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Predisposition; Prevention; Process; Qualifying; Research; Risk; Risk Reduction; Role; Senile Plaques; Series; Serotonergic System; Serotonin; Serotonin Receptor 5-HT2B; Synapses; Synaptic plasticity; System; Therapeutic; Toxic effect; Toxicology; Withdrawal; analog; antagonist; behavioral outcome; cholinergic; clinical trial readiness; comparative; effective therapy; efficacy validation; first-in-human; genetic association; high risk; neglect; neuron loss; noradrenergic; novel; pharmacologic; pre-clinical; preclinical development; preclinical evaluation; preclinical safety; research clinical testing; resilience; response; screening; small molecule; small molecule inhibitor; small molecule therapeutics; spatial memory; success; synaptic function; tau Proteins; therapeutic candidate; therapeutic evaluation; therapeutic target

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，但没有 疾病改变干预措施。先前临床试验失败的根本原因为计划提供了指导 重振AD/ADRD热发现和开发过程。具体而言，多元化的投资组合 根据临床观察，遗传关联，可获得候选治疗方法 病理结局和生化机制。但是，许多人在资金和 技术追求。可以通过保留治疗性来避免对基于病理的途径的先前强调 强调病理生理进展机制的离散但互补方面。突触 功能障碍是潜在潜在目标的一个例子。突触功能障碍是微妙的失忆症的基础 在经典组织病理学标志发展之前发生的变化。突触恶化 加强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，多巴胺能和血清素能系统。血清素能系统既是一个未充满震动的 考虑到5-羟色胺不仅仅是神经递质，并且考虑到治疗机制，并且特别有吸引力。 此外，AD患者中5-羟色胺受体2B（5-HT2BR）表达增加的临床发现 大脑和AD患者对非选择性5-HT2BR拮抗剂的反应表明， 在AD中优化了5-HT2BR拮抗剂。我们开发了一个小分子MW01-8-071HAB（= MW071）， 抑制LTP缺陷以及淀粉样蛋白β（Aβ）和TAU模型中的联想和空间记忆 海拔。具有158个已知GPCR的脱靶激动剂和拮抗剂活性的功能性筛选 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。具有5-HT2BR激动剂活性的批准药物具有高风险 心脏瓣膜毒性，导致戒断或黑匣子警告。因此，AD的有希望的效率 相关模型，一种在没有高度选择性拮抗剂活动的情况下的药物剖面 激动剂活动，备用候选者的可用性（MW109）增加了MW071的整体外观 起点。我们提出的早期研究将进一步脱离风险MW071和MW109，以生成 并符合候选人的候选人的未来后期U01申请： 目标1。在FDA指导之后进行二级药理学分析，作为必要的前奏和公司 未来的GXP基金会促进临床前安全和毒理学研究。 目标2。验证MW071和MW109在预防/逆转突触和记忆中的效率 与广告相关的动物模型中的障碍。 定量里程碑将通过GO/NO GO决策点确定进展。成功的结果 和可交付成果将允许将来对GXP成立评估和人类首次评估的支持。