Discovery of functionally selective Alzheimer's disease therapeutics

摘要 阿尔茨海默病(AD)的患病率以及相关的经济和照顾者负担预计将不断上升 除非发现可以改变疾病的治疗方法，否则这将是戏剧性的。我们的研究集中在解决这一紧迫的未得到满足的问题上 通过发现和开发能够避免或延迟的药物疗法来满足医疗和社会需求 AD的进展。由慢性氧化-亚硝化应激引发的脑部炎症是已证实的 致病级联导致轻度认知障碍(MCI)和阿尔茨海默病。当过量的炎症性一氧化氮和 超氧化物分子结合在一起，形成了损害大脑的活性物种过氧亚硝酸盐。这种情况将永久化 炎症导致在AD中观察到的进行性神经变性。我们的创新方法包括 管理与炎症性疾病进展相关的两个过程。第一个涉及到中断循环 通过抑制氧化应激引发的一氧化氮中不安全的升高来产生过氧亚硝酸盐，以及第二种 包括通过促进脑源性激素的分泌来增强对炎性侮辱的抵抗力和恢复能力 神经营养因子(BDNF)。单一的应激激活的伴侣蛋白在机械上能够同时调节 促炎症状态下脑源性神经营养因子的分泌和一氧化氮水平的调节。初步研究已经确定 进一步开发中枢神经系统药物的化学型起点，这些起点具有所需的双重功能选择性 这种靶标受体。我们的计划是优化这些功能选择性化学类型的中枢神经系统类药物特性 开发能够显著改变MCI/AD病程的药物的目标。

Abstract The prevalence of Alzheimer's disease (AD) and the associated financial and caregiver burden is projected to escalate dramatically unless disease-modifying treatments are discovered. Our research is focused on addressing this urgent unmet medical and societal need through the discovery and development of pharmacotherapies capable of averting or delaying the progression of AD. Brain inflammation initiated by chronic oxidative-nitrosative stress is a proven component of the pathogenic cascade leading to mild cognitive impairment (MCI) and AD. When surplus inflammatory nitric oxide and superoxide molecules combine they form the brain-impairing reactive species peroxynitrite. This perpetuates inflammation resulting in the progressive neurodegeneration observed in AD. Our innovative approach consists of managing two processes associated with inflammatory disease progression. The first involves interrupting the cycle of peroxynitrite generation by suppressing unsafe elevations in nitric oxide triggered by oxidative stress, and the second involves enhancing resilience to and recovery from inflammatory insults by facilitating the secretion of brain-derived neurotrophic factor (BDNF). A single stress-activated chaperone protein is mechanistically capable of both mediating BDNF secretion and regulating nitric oxide levels under proinflammatory conditions. Preliminary studies have identified chemotype starting points for further CNS drug development which have the desired dual functional selectivity profile for this target receptor. Our plan is to optimize the CNS drug-like properties of these functionally selective chemotypes with the goal of developing medicines that can significantly modify the course of MCI/AD.