Novel sigma-2 receptor modulators for the treatment of cognitive dysfunction

用于治疗认知功能障碍的新型 sigma-2 受体调节剂

• 批准号: 9047387
• 负责人: NICHOLAS John IZZO
• 金额: $ 29.85万
• 依托单位: COGNITION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047387
• 关键词: Acute; Affinity; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Attention; Base of the Brain; Binding; Bioavailable; Biochemical; Biological Assay; Biological Availability; Bolus Infusion; Brain; CYP2C9 gene; CYP2D6 gene; CYP3A4 gene; Cells; Clinical; Clinical Trials; Cognition; Collaborations; Data; Development; Disease; Disease Progression; Dose; Drug Industry; Drug Kinetics; Event; Exhibits; Feasibility Studies; Feedback; Functional disorder; Funding; Future; Goals; Hepatocyte; Impaired cognition; In Vitro; Inhibitory Concentration 50; Lead; Ligands; Measurement; Measures; Mediating; Membrane Protein Traffic; Memory; Memory impairment; Metabolic; Mission; Modification; Mus; Neurons; Oral; Oral Administration; Pathology; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Preparation; Process; Production; Property; Proteins; Recovery; Research Personnel; Risk; Series; Serotonin; Signal Transduction; Solubility; Specific qualifier value; Symptoms; Synapses; Testing; Therapeutic; Transgenic Animals; Universities; Water; Work; abeta oligomer; analog; aqueous; base; design; drug development; improved; in vivo; iterative design; lead series; meetings; member; mild cognitive impairment; mouse model; novel; novel therapeutics; phase 1 study; preclinical study; prevent; professor; public health relevance; receptor; receptor binding; risk mitigation; screening; sigma-2 receptor; small molecule; trafficking

 DESCRIPTION (provided by applicant): Cognition Therapeutics Inc.'s mission is to develop effective therapeutics for Alzheimer's disease (AD). Recent scientific discoveries have identified oligomers of the brain protein Aβ42 as toxic culprits in disease progression. Cognition, in partnership with Temple University, has identified a novel series of sigma-2 receptor binding modulators that displace oligomers from neurons and block the downstream pathological signaling that inhibits memory formation. These therapeutics should prevent further Aβ42 oligomer-induced damage, and unmask existing memory capacity as synapses recover. These receptor binding modulators are hypothesized to be disease-modifying treatments that would be effective throughout the course of the disease, and significantly impact the lives of the millions of Alzheimer's patients. Pharmaceutical industry efforts targeted specifically at Aβ42 oligomer displacement are currently limited. Cognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule Aβ42 oligomer displacing therapeutics. We have discovered two CNS drug-like lead series of Aβ42 oligomer displacing compounds, Analogs in these series displace oligomers from neurons and completely block Aβ42 oligomer-induced membrane trafficking changes and synapse loss. Members of these series are highly brain-penetrant and completely block oligomer-induced memory deficits in Alzheimer's disease mouse models. Development of a clinical candidate is progressing. We have now turned our attention to identifying new candidates to provide a measure of risk mitigation in the event that our current candidate falters due to unforeseen issues. We propose to optimize Temple University's series of novel sigma-2 receptor binding modulators by synthesis and testing of new analogs designed to improve pharmacological and ADME properties. This proposal will allow us to expand our portfolio of sigma-2 receptor binding modulators with the goal of identifying orally efficacious candidates for further development as therapeutics for AD.

 描述（由申请人提供）：Cognition Therapeutics Inc.的使命是开发有效的治疗阿尔茨海默病（AD）的药物。最近的科学发现已经确定脑蛋白Aβ42的寡聚体是疾病进展的毒性罪魁祸首。Cognition与坦普尔大学合作，已经确定了一系列新的sigma-2受体结合调节剂，这些调节剂可以取代神经元中的低聚物，并阻断抑制记忆形成的下游病理信号传导。这些疗法应该可以预防Aβ42寡聚体诱导的进一步损伤，并随着突触的恢复而揭示现有的记忆能力。这些受体结合调节剂被假设为在整个疾病过程中有效的疾病修饰治疗，并显著影响数百万阿尔茨海默病患者的生活。目前，制药行业专门针对Aβ42低聚物置换的努力有限。Cognition Therapeutics是唯一专注于发现小分子Aβ42寡聚体替代疗法的公司之一。我们发现了两个中枢神经系统药物样的Aβ42寡聚体置换先导化合物系列，这两个系列的类似物从神经元中置换寡聚体，并完全阻断Aβ42寡聚体诱导的膜运输变化和突触丢失。这些系列的成员具有高度的脑渗透性，并完全阻断阿尔茨海默病小鼠模型中寡聚体诱导的记忆缺陷。临床候选人的开发正在进行中。我们现在已经将注意力转向确定新的候选人，以便在我们目前的候选人因不可预见的问题而动摇的情况下，提供一种减轻风险的措施。我们建议通过合成和测试旨在改善药理学和ADME特性的新类似物来优化坦普尔大学的一系列新型sigma-2受体结合调节剂。这一提议将使我们能够扩大我们的σ-2受体结合调节剂的产品组合，目标是鉴定口服有效的候选物，以进一步开发为AD的治疗剂。

项目成果

Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands.

• DOI: 10.3390/ijms23158259
• 发表时间: 2022-07-27
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Xu, Kuiying;Hsieh, Chia-Ju;Lee, Ji Youn;Riad, Aladdin;Izzo, Nicholas J.;Look, Gary;Catalano, Susan;Mach, Robert H.
• 通讯作者: Mach, Robert H.