Developing a NAMPT activator for Alzheimer’s disease

开发治疗阿尔茨海默病的 NAMPT 激活剂

• 批准号: 10736017
• 负责人: Beibei Chen
• 金额: $ 238.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736017
• 关键词: Acceleration; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Animal Model; Animals; Binding; Biological Assay; Biological Markers; Brain; Cells; Chemicals; Chemistry; Chronology; Clinical; Clinical Trials; Data; Data Set; Dependence; Development Plans; Disease; Dose; Enzymes; Exhibits; Future; Goals; Human; Impaired cognition; Late Onset Alzheimer Disease; Lead; Legal patent; Libraries; Ligand Binding; Metabolism; Modeling; Mus; Nerve Degeneration; Neurons; Nutraceutical; Pathway interactions; Patients; Phase I Clinical Trials; Population; Pre-Clinical Model; Preclinical Testing; Qualifying; Research Personnel; Risk Factors; Route; Series; Serum; Sodium Chloride; Technology; Testing; Therapeutic Index; Tissues; Toxicology; Validation; age related; aging brain; blood-based biomarker; clinical candidate; cognitive function; drug development; drug discovery; experience; human subject; improved; in vivo; induced pluripotent stem cell; innovation; lead optimization; manufacture; manufacturing scale-up; mild cognitive impairment; mouse model; nicotinamide phosphoribosyltransferase; novel; pharmacologic; phase 1 testing; pre-clinical; preclinical efficacy; prevent; programs; scale up; screening; small molecule; targeted biomarker; uptake

Currently there are no therapies that can slow or reverse the cognitive decline seen in late-onset Alzheimer's disease (LOAD). The single greatest risk factor for this condition is chronological age and as the global population ages, the number of AD cases is expected to continue to rapidly increase. This age-dependent association has led many to suggest that strategies that slow or reverse aspects of brain aging might be of particular use in patients with LOAD. In normal human subjects, there is an age-dependent decline in brain NAD+ levels and in animal models, a decline in brain NAD+ is strongly associated with aging and cognitive decline, while restoring NAD+ can improve cognitive function. Moreover, evidence suggests that in pre-clinical AD models, there is an accelerated loss of NAD+ and that neurons are particularly vulnerable to a reduction in intracellular NAD+ levels. It is well established that the rate limiting enzyme in the NAD salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT) and that the enzymatic activity of NAMPT largely determines the level of NAD+ within cells. Here, we describe an early stage drug development proposal to advance a brain penetrant, small molecule that augments NAMPT activity, thus increasing neuronal NAD+ levels and combating brain aging. We describe the development plan of this molecule up to the IND filing stage. The ultimate clinical indication for such a molecule would be in patients with LOAD and mild cognitive impairment. We have assembled a team with extensive drug development and AD experience, both in the pre-clinical and clinical arena. This proposal describes a series of milestones and go/no go decision points to advance our current set of three distinct chemical series, all of which directly bind to NAMPT and increase enzymatic activity, to a single final clinical candidate that would be ready to advance to Phase I testing in human subjects. This compound would be a first- in-class small molecule that seeks to reverse the age-dependent decline in NAD+ levels as a means to treat mild cognitive impairment in LOAD patients.

目前，没有疗法可以减慢或扭转阿尔茨海默氏症的认知能力下降 疾病（负载）。这种情况的最大风险因素是按时间顺序排列的，并且是全球人口 年龄，预计AD病例的数量将继续迅速增加。这个与年龄有关的关联有 导致许多人暗示，脑老化的缓慢或反向的策略可能特别使用 负载患者。在正常的人类受试者中，脑NAD+水平的年龄依赖性下降和 动物模型，脑NAD+的下降与衰老和认知能力下降密切相关，同时还原 NAD+可以提高认知功能。此外，有证据表明，在临床前广告模型中，有一个 NAD+的加速损失，并且神经元特别容易受到细胞内NAD+水平的降低。 众所周知，NAD打捞途径中限制速率的酶是烟酰胺 磷酸贝糖基转移酶（NAMPT），NAMPT的酶活性在很大程度上决定了 细胞内的NAD+。在这里，我们描述了一项早期药物开发建议，以提高脑部渗透剂， 增加NAMPT活性的小分子，从而增加了神经元NAD+水平并打击脑衰老。 我们将该分子的开发计划描述为IND归档阶段。最终的临床指示 这样的分子将在负荷和轻度认知障碍的患者中。我们已经组建了一个团队 在临床前和临床领域，具有广泛的药物开发和广告经验。这个建议 描述了一系列里程碑和go/no go决策点，以推动我们当前的三个不同的不同 化学系列，所有这些系列都直接与NAMPT结合并增加酶促活性，与单个最终临床 准备好在人类受试者中进行I期测试的候选人。该化合物将是首先 旨在扭转NAD+水平年龄依赖性下降的班级小分子作为治疗轻度的一种手段 负载患者的认知障碍。