Optimization of small molecule SERCA2b activators to inhibit neuron loss in Alzheimer's disease

优化小分子 SERCA2b 激活剂抑制阿尔茨海默病神经元损失

• 批准号: 10080109
• 负责人: Russell Dahl
• 金额: $ 98.89万
• 依托单位: NEURODON LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080109
• 关键词: APP-PS1; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer’s disease biomarker; Animal Model; Apoptosis; Apoptotic; Behavioral; Behavioral Model; Biological; Biological Assay; Biological Availability; Biology; Brain; Ca(2+)-Transporting ATPase; Cardiovascular Diseases; Cause of Death; Cell Culture Techniques; Cell Death; Cell model; Cells; Chemicals; Chemistry; Cholinesterase Inhibitors; Clinic; Clinical; Clinical Trials; Cognition; Cognitive; Cytoplasm; Dementia; Development; Disease; Disease Progression; Dose; Endoplasmic Reticulum; Equilibrium; Goals; Grant; Hippocampus (Brain); In Vitro; Intervention; Lead; Legal patent; Link; Malignant Neoplasms; Measures; Memantine; Memory; Memory Loss; Mutagenicity Tests; Nerve Degeneration; Neurons; Neurotransmitters; Oral; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Probability; Property; Protein Isoforms; Proteins; Public Health; Pump; Research; Risk; Senile Plaques; Series; Short-Term Memory; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Structure; Symptoms; Synthesis Chemistry; Testing; Therapeutic; Transgenic Mice; United States; Universities; Work; biomarker-driven; brain cell; candidate identification; drug discovery; endoplasmic reticulum stress; flexibility; improved; in vitro Model; in vitro activity; in vivo; insight; lead candidate; lead optimization; mouse model; neuron apoptosis; neuron loss; neuroprotection; novel; patient population; physical property; positive allosteric modulator; preservation; prevent; programs; response; scaffold; screening; small molecule; spatial memory; success; transgenic model of alzheimer disease

Neurodon LLC proposes to conduct lead optimization and candidate-seeking activities on a novel series of neuroprotective small molecules that shows efficacy in a transgenic model of Alzheimer’s disease (AD). AD is a leading cause of death in the United States, with some estimates ranking it as high as third behind cardiovascular disease and cancer. Despite the enormity of this national public health burden, the therapeutic options are very limited. The few approved therapies treat only symptoms, and there are no disease-modifying therapies approved. All of the recent clinical trials have failed or are not meeting efficacy endpoints. With this patient population set to almost triple over the next 30 years, there is a dire need for disease-modifying therapies. Neuron loss is the only physiological phenomena that has been directly linked to the cognition and memory loss in patients, and a major cause of brain cell death in AD is endoplasmic reticulum (ER) stress- induced apoptosis caused by intracellular Ca2+ dyshomeostasis. Neurodon’s patented, small molecule positive allosteric modulators (PAMs) of the major ER Ca2+ handling protein, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), rescue brain cells in vitro and in vivo, improve memory and cognition in the APP/PS1 double transgenic mouse model of AD, and reduce ER stress markers in vivo, enabling biomarker-driven drug discovery and an improved probability of clinical success. Our Phase 1 research met the technical milestone of developing molecules with improved in vitro profiles when compared to our previous proof-of-concept compounds. We developed 5 new PAMs with improved efficacy in an in vitro Alzheimer’s model, sub- micromolar potencies in neuroprotection assays, and improved physicochemical properties. In this proposal, we will again partner with the medicinal chemistry expertise and facilities at Northwestern University. We have also added additional experts to the team in Alzheimer’s models, SERCA biology, and behavioral animal models. Our goal of identifying development molecules for Alzheimer’s disease will be accomplished by pursuing the following Aims: 1) Perform lead optimization of SERCA2b PAMs via iterative medicinal chemistry synthesis. 2) Perform in vitro profiling in neuroprotective and synaptoprotective assays to measure potency and efficacy of SERCA2b PAMs. 3) Perform candidate-seeking activities to identify SERCA2b PAMs with drug- like properties. 4) Perform essential in vivo characterization studies on lead SERCA PAMs in the APP/PS1 transgenic mouse model of AD. The results of these Aims will be the identification of candidate molecules to progress into IND-enabling studies at Neurodon.

Neurodon有限责任公司建议进行铅优化和候选人寻找活动的一个新的系列， 在阿尔茨海默病（AD）的转基因模型中显示功效的神经保护性小分子。AD是 这是美国的一个主要死因，据估计，它排在第三位， 心血管疾病和癌症。尽管这一国家公共卫生负担的艰巨性， 选择非常有限。少数被批准的治疗方法只治疗症状，没有改善疾病的方法。 批准的治疗。所有最近的临床试验都失败或不符合疗效终点。与此 在未来30年内，患者人数将增加近两倍，因此迫切需要改变疾病 治疗神经元损失是唯一与认知直接相关的生理现象， AD患者的记忆丧失，以及AD中脑细胞死亡的主要原因是内质网（ER）应激- 诱导细胞内Ca ~（2+）稳态失调引起的细胞凋亡。Neurodon的专利，小分子阳性 主要ER Ca 2+处理蛋白，肌浆网/内质网Ca 2 +-ATP酶的变构调节剂（PAM） （SERCA），在体外和体内拯救脑细胞，在APP/PS1双重作用下改善记忆和认知 AD转基因小鼠模型，并降低体内ER应激标志物，使生物标志物驱动的药物 发现和提高临床成功的可能性。我们的第一阶段研究达到了技术里程碑， 与我们以前的概念验证相比，开发具有改进的体外特征的分子 化合物.我们开发了5种新的PAM，在体外阿尔茨海默病模型中具有改善的功效， 在神经保护测定中的微摩尔效力，以及改进的物理化学性质。在这项提案中， 我们将再次与西北大学的药物化学专业知识和设施合作。我们有 还增加了阿尔茨海默病模型，SERCA生物学和行为动物方面的专家 模型我们确定阿尔茨海默病的发育分子的目标将通过以下方式实现： 追求以下目标：1）通过迭代药物化学进行SERCA 2b PAM的电极导线优化 合成. 2)在神经保护和突触保护试验中进行体外分析，以测量效力 和SERCA 2b PAM的功效。3)进行候选人寻找活动，以识别具有药物的SERCA 2b PAM- 比如财产4)对APP/PS1中的电极导线SERCA PAM进行必要的体内表征研究 AD的转基因小鼠模型。这些目标的结果将是鉴定候选分子， 在Neurodon进行IND研究。