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.

目前还没有任何疗法可以减缓或逆转晚发性阿尔茨海默氏症的认知能力下降 疾病（负荷）。这种情况的最大风险因素是实际年龄，并且随着全球人口的增长 随着年龄的增长，AD 病例数量预计将继续快速增加。这个依赖于年龄的协会 导致许多人认为减缓或逆转大脑衰老的策略可能在以下方面特别有用： 负载患者。在正常人类受试者中，大脑 NAD+ 水平存在年龄依赖性下降，并且 动物模型中，大脑 NAD+ 的下降与衰老和认知能力下降密切相关，同时恢复 NAD+可以改善认知功能。此外，有证据表明，在临床前 AD 模型中，存在 NAD+ 加速丢失，神经元特别容易受到细胞内 NAD+ 水平降低的影响。 众所周知，NAD 挽救途径中的限速酶是烟酰胺 磷酸核糖基转移酶（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提案，以推进脑渗透剂， 增强 NAMPT 活性的小分子，从而增加神经元 NAD+ 水平并对抗大脑衰老。 我们描述了该分子直至 IND 申请阶段的开发计划。最终临床适应症 这种分子将用于患有 LOAD 和轻度认知障碍的患者。我们已经组建了一个团队 在临床前和临床领域拥有丰富的药物开发和 AD 经验。这个提议 描述了一系列里程碑和继续/不继续决策点，以推进我们当前的三个不同的组 化学系列，所有这些都直接与 NAMPT 结合并增加酶活性，以达到单一的最终临床效果 准备好进入人体第一阶段测试的候选人。该化合物将是第一个 同类小分子，旨在逆转 NAD+ 水平随年龄的下降，作为治疗轻度症状的方法 LOAD 患者的认知障碍。