New piperazines effecting Abeta oligomer displacement from neuronal receptors

 描述(申请人提供)：认知治疗公司S的使命是开发治疗阿尔茨海默病的有效疗法。最近的科学发现发现，大脑蛋白Abeta42的寡聚体是疾病过程中的有毒罪魁祸首。认知已经发现了治疗分子，它可以取代神经元中的Aβ寡聚体，并阻止下游抑制记忆形成的病理信号。这些治疗性的小分子应该可以防止低聚物引起的进一步损伤，并在突触恢复时揭示现有的记忆能力。这些分子通过调节一个新识别的受体靶点来发挥作用。它们被假设为疾病修正治疗，在整个疾病过程中都有效，并显著影响数百万阿尔茨海默氏症患者的生活。制药业专门针对Aβ齐聚物封锁的努力目前有限。认知治疗公司是唯一一家专注于发现小分子低聚物置换疗法的公司之一。我们发现了一种CNS类药物取代齐聚物的先导系列化合物，CT0109系列。这一系列的类似物取代了神经元中的寡聚体，并完全阻断了Abeta寡聚体诱导的膜转运变化和突触丢失。这一系列的成员是高度脑渗透性的，并完全阻断低聚物诱导的阿尔茨海默病小鼠模型的记忆缺陷。这些类似物的进一步临床前开发正在取得进展。然而，具有不同物理化学特征的新结构变体将在我们目前的候选人因不可预见的问题而未能通过临床的情况下提供一种风险缓解措施。我们建议探索CT0109系列的一种新的哌嗪变种。这种新的变种将拥有本系列以前未曾探索过的物理化学特性。这项建议将使我们能够扩大我们的Abeta齐聚物置换化合物的产品组合，并确定这些变体进行优化的可行性，目标是获得口服有效的候选药物，用于进一步开发用于治疗AD的药物。

 DESCRIPTION (provided by applicant): Cognition Therapeutics Inc.'s mission is to develop effective therapeutics for Alzheimer's disease. Recent scientific discoveries have identified oligomers of the brain protein Abeta 42 as toxic culprits in the disease process. Cognition has discovered therapeutic molecules that displace Abeta oligomers from neurons and block the downstream pathological signaling that inhibits memory formation. These therapeutic small molecules should prevent further oligomer-induced damage, and unmask existing memory capacity as synapses recover. These molecules act through modulating a newly identified receptor target. They are hypothesized to be disease-modifying treatments that would be effective throughout the course of the disease, and significantly impact the lives of millions of Alzheimer's patients. Pharmaceutical industry efforts targeted specifically at Abeta oligomer blockade are currently limited. Cognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule oligomer-displacing therapeutics. We have discovered a CNS drug-like lead series of oligomer-displacing compounds, the CT0109 Series. Analogs in this series displace oligomers from neurons and completely block Abeta oligomer-induced membrane trafficking changes and synapse loss. Members of this series are highly brain-penetrant and completely block oligomer-induced memory deficits in Alzheimer's disease mouse models. Further preclinical development of these analogs is progressing. However, new structural variants with different physicochemical profiles will provide a measure of risk mitigation in the event that our current candidates fail to advance through the clinic due to unforeseen issues. We propose to explore a new piperazine variant of the CT0109 series. This new variant would possess physiochemical properties previously unexplored in the current series. This proposal will allow us to expand our portfolio of Abeta oligomer-displacing compounds and establish the feasibility of these variants to be optimized with the goal of obtaining orally efficacious candidates for further development as therapeutics for AD.