Nomethiazoles Harnessing GABA and NO mimetic activity for Alzheimer's therapy

描述(申请人提供)：阿尔茨海默病(AD)发生在八分之一的65岁的美国人，并影响43%的85岁以上的老年人。目前FDA批准的药物只提供AD的症状缓解。目前迫切需要发现新的治疗疾病的药物。广告的起源和发展是多因素的。一种能减弱几种潜在因素的药物是治疗阿尔茨海默病的首选疗法。Nomethiazoles是一类小分子，通过NO/cGMP信号转导解决突触功能障碍，并利用甲基噻唑(MZ)药效团的神经保护和GABA模拟活性。NO/cGMP/CREB信号通路的激活对学习和记忆至关重要，已知在AD大脑中会减弱。MZ药效团提供神经保护，防止大脑中的兴奋性毒性和抗炎作用。初步数据显示，在AD转基因小鼠模型中，诺甲噻唑可以逆转认知缺陷，减缓A？的积累，并提供积极的生物标志物：四种诺甲噻唑已被确定为AD治疗的有希望的先导。选择首选的候选药物和用于开发的后备化合物是这项STTR第一阶段研究的主要目标。在目标1中，将制备最佳的诺甲噻唑类药物盐。在目标2中，候选药物的选择将以药物代谢和药代动力学(DMPK)研究为指导。将研究人/啮齿动物血浆和肝微粒体中的稳定性，并在脑和血浆中建立脑组织和血浆中诺美噻唑和MZ代谢物的PK谱。投递到老鼠身上。在目标3中，将收集有关先兆认知、缓解焦虑和镇静效果的行为数据，以确定先兆认知和镇静效力之间的治疗窗口。AIMS 2和AIMS 3的数据比较将提供PK/PD相关性。计划中的STTR2期研究的目标是在启动全面的IND-Enabling ADMET研究之前，通过收集更多的有效性和安全性数据来降低临床失败的风险。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) occurs in one out of eight Americans of age 65 and affects 43% of the elderly over 85. Current FDA-approved drugs only provide symptomatic relief of AD. There is a pressing need to discover new disease-modifying medications. AD is multifactorial in origin and progression. A drug attenuating several underlying factors is a preferred therapy for AD. Nomethiazoles are a class of small molecules that address synaptic dysfunction through NO/cGMP signaling and harness the neuroprotective and GABA-mimetic activities of a methylthiazole (MZ) pharmacophore. Activation of the NO/cGMP/CREB signaling oathway, essential for learning and memory, is known to be attenuated in AD brains. The MZ pharmacophore provides neuroprotection against excitotoxicity and anti-inflammatory actions in the brain. Preliminary data show that nomethiazoles reverse cognitive deficits, slow A¿ accumulation, and provide a positive biomarker profile in AD transgenic mouse models: four nomethiazoles have been identified as promising leads for AD therapy. Selection of the preferred drug candidate and a back-up compound for development is the major objective of this STTR phase I study. Optimal pharmaceutical salts of nomethiazoles will be prepared in Aim 1. In Aim 2, drug candidate selection will be guided by drug metabolism and pharmacokinetics (DMPK) studies. Stability in human/rodent plasma and liver microsomes will be investigated and PK profiles generated for nomethiazole and MZ metabolite in brain and plasma after i.p. delivery to mice. In Aim 3, behavioral data will be collected on procognitive, anxiolytic, and sedative effects, to determine the therapeutic window between procognitive and sedative potency. Data comparison of Aims 2 and 3 will provide PK/PD correlations. The objective of planned STTR phase 2 studies is to reduce the risk of failure in the clinic by collecting further efficacy and safety data prior to launching full IND-enabling ADMET studies.