Development of Nav1.1 Enhancers to Treat Alzheimer's Disease

摘要 CNDAP正在开发一种新的药物类别，通过一种独特的作用机制发挥作用，以逆转早期 阿尔茨海默病(AD)的病理生理和认知改变。最近的研究表明， 网络功能障碍，包括网络多动，振荡节律改变，以及过度兴奋 同步网络，是在AD的临床前模型和患者中发现的早期致病事件 AD的早期阶段。网络功能障碍导致认知异常、抗体和tau蓄积，以及 神经退行性变。在动物模型中，网络功能障碍可以通过加强抑制来恢复 (GABA能)中间神经元依赖的伽马节律，通过光遗传/感觉刺激或基因 Nav1.1的过度表达。AD模型中伽马节律的恢复导致淀粉样蛋白减少 Tau沉积、神经变性、小胶质细胞和星形胶质细胞激活、炎症、神经血管 改变、AD诱导的全基因组转录改变、振荡活动改变和认知 拒绝。因为钠通道Nav1.1的过度表达只有25%可以恢复伽马节律 到AD模型的正常水平，我们正在开发小分子疗法，旨在安全地增加 治疗阿尔茨海默病的脑内Nav1.1活动。我们已经确定了几种小分子化学类型，它们有效地 增强细胞系中的人类Nav1.1电流和脑片中的中间神经元依赖的伽马振荡。 在小鼠体内全身注射大剂量的Nav1.1增强剂没有明显的效果 毒性或行为副作用，但显著增加内源性伽马振荡活性 野生型小鼠，这表明我们的化合物是脑穿透的，可能有以下有益的影响 系统性管理。在这项快速通道SBIR授权中，我们建议进一步开发Nav1.1增强功能，以 治疗AD。在第一阶段的研究中，我们将使用药物化学和SAR分析来确定结构 独特、高效和选择性的Nav1.1增强剂，以扩大我们的物质化学成分。 药代动力学和脑生物利用度分析将用于选择最有效的化合物 最佳的药用性能。我们实现进入第二阶段研究的里程碑是识别 至少一种结构新颖的Nav1.1增强剂，其选择性且显著地增加伽马 大脑中的体外振荡。第二阶段研究旨在确定我们的体外和体内疗效 Nav1.1增强剂通过其预防的能力恢复临床前AD小鼠模型中的网络功能障碍 网络超同步和异常振荡活动，恢复全基因组转录变化和 减少认知障碍、神经病理和提高存活率，以支持他们未来的发展 治疗AD患者。

ABSTRACT CNDAP is developing a new class of drugs, acting through a unique mechanism of action, to reverse early pathophysiological and cognitive alterations in Alzheimer’s disease (AD). Recent studies indicate that network dysfunction, which includes network hyperactivity, altered oscillatory rhythms, and hyper- synchronized networks, is an early pathogenic event found in preclinical models of AD and in patients with early stages of AD. Network dysfunction contributes to cognitive abnormalities, Ab and tau accumulation, and neurodegeneration. In animal models, network dysfunction can be restored by enhancing inhibitory (GABAergic) interneuron-dependent gamma rhythms via optogenetic/sensory stimulation or genetic overexpression of Nav1.1. This restoration of gamma rhythms in the AD models leads to reduced amyloid and tau deposition, neurodegeneration, microglia and astrocytic activation, inflammation, neurovascular alterations, AD-induced genome-wide transcriptomics changes, altered oscillatory activity, and cognitive decline. Because overexpression of the sodium channel Nav1.1 by as little as 25% restores gamma rhythms to normal levels in AD models, we are developing small molecule therapeutics designed to safely increase Nav1.1 activity in the brain to treat AD. We have identified several small molecule chemotypes that effectively enhance human Nav1.1 currents in cell lines and interneuron-dependent gamma oscillations in brain slices. Systemic intraperitoneal administration of high doses of a Nav1.1 enhancer in vivo in mice produced no overt toxicity or behavioural side effects but significantly increased endogenous gamma oscillatory activity in wildtype mice, suggesting that our compounds are brain penetrant and may have beneficial effects following systemic administration. In this fast-track SBIR grant, we propose to further develop Nav1.1 enhancers to treat AD. In Phase 1 studies, we will employ medicinal chemistry and SAR analysis to identify structurally unique, potent and selective Nav1.1 enhancers to expand our chemical composition of matter. Pharmacokinetics and brain bioavailability analyses will be used to select the most active compounds with optimal pharmaceutical properties. Our milestone to achieve to move to Phase 2 studies is the identification of at least one structurally novel Nav1.1 enhancer that selectively and significantly increases gamma oscillations ex vivo in brain. Phase 2 studies are designed to establish the ex vivo and in vivo efficacy of our Nav1.1 enhancers to restore network dysfunction in preclinical AD mouse models by their ability to prevent network hypersynchrony and abnormal oscillatory activity, restore genome-wide transcriptomic changes and to reduce cognitive impairment, neuropathology and improve survival to support their future development to treat AD patients.