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

诺美噻唑利用 GABA 和 NO 模拟活性治疗阿尔茨海默病

• 批准号: 8590612
• 负责人: Gregory R. J Thatcher
• 金额: $ 14.98万
• 依托单位: SGC PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8590612
• 关键词: APP-PS1; Address; Affect; Age; Aging; Alzheimer' s Disease; American; Animal Model; Anti-Anxiety Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antihypertensive Agents; Apolipoprotein E; Attenuated; Back; Behavioral; Behavioral Assay; Biological Assay; Biological Markers; Brain; Businesses; CREB1 gene; Chimera organism; Clinic; Clinical; Clinical Trials; Cognitive deficits; Coin; Correlation Studies; Cyclic GMP; Data; Development; Disease; Disease Progression; Dissociation; Dose; Drug Design; Drug Formulations; Drug Kinetics; Elderly; FDA approved; Failure; Functional disorder; Future; Genotype; Grant; Human; In Vitro; Intellectual Property; Lead; Learning; Liver Microsomes; Measures; Memory; Metabolism; Mission; Mus; Neurodegenerative Disorders; Neurologic; Neuroprotective Agents; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma; Play; Powder dose form; Preparation; Process; Property; Rattus; Risk; Risk Factors; Rodent; Safety; Salts; Scopolamine; Signal Transduction; Small Business Technology Transfer Research; Sodium Chloride; Staging; Synapses; TNF gene; Testing; Therapeutic; Therapeutic Agents; Time; Transgenic Mice; United States National Institutes of Health; Water; apolipoprotein E-4; attenuation; base; candidate selection; design; drug candidate; drug metabolism; excitotoxicity; gamma-Aminobutyric Acid; in vivo; in vivo Model; mimetics; mouse model; neuroprotection; novel; particle; pharmacophore; phase 1 study; phase 2 study; pre-clinical; preclinical efficacy; preclinical safety; prototype; public health relevance; research study; safety study; sedative; small molecule

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.

描述（由申请人提供）： 65 岁美国人中，八分之一的人患有阿尔茨海默病 (AD)，影响 85 岁以上老年人的 43%。目前 FDA 批准的药物只能缓解 AD 症状。迫切需要发现新的疾病缓解药物。 AD 的起源和进展是多因素的。减轻多种潜在因素的药物是治疗 AD 的首选疗法。诺美噻唑是一类小分子，可通过 NO/cGMP 信号传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。众所周知，对于学习和记忆至关重要的 NO/cGMP/CREB ​​信号通路的激活在 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，诺美噻唑可逆转认知缺陷，减缓 A¿ 积累，并在 AD 转基因小鼠模型中提供积极的生物标志物特征：四种诺美噻唑已被确定为 AD 治疗的有希望的先导药物。选择首选候选药物和备用化合物进行开发是本 STTR I 期研究的主要目标。目标 1 将制备诺美噻唑的最佳药用盐。目标 2 将通过药物代谢和药代动力学 (DMPK) 研究指导候选药物的选择。将研究人类/啮齿动物血浆和肝微粒体的稳定性，并生成腹腔注射后脑和血浆中诺美噻唑和 MZ 代谢物的 PK 曲线。交付给老鼠。在目标 3 中，将收集有关促认知、抗焦虑和镇静作用的行为数据，以确定促认知和镇静效力之间的治疗窗口。目标 2 和 3 的数据比较将提供 PK/PD 相关性。计划的 STTR 第 2 期研究的目标是在启动全面的 IND 支持的 ADMET 研究之前收集进一步的疗效和安全性数据，以降低临床失败的风险。