Developing a NAMPT activator for Alzheimer’s disease

目前还没有治疗方法可以减缓或逆转迟发性阿尔茨海默氏症的认知能力下降 疾病（负载）。这种情况的单一最大风险因素是实足年龄， 随着年龄的增长，AD病例的数量预计将继续迅速增加。这种年龄依赖性的关联 导致许多人认为，减缓或逆转大脑衰老的策略可能特别适用于 患者负荷。在正常人类受试者中，脑NAD+水平和脑内NAD+水平存在年龄依赖性下降。 在动物模型中，大脑NAD+的下降与衰老和认知能力下降密切相关， NAD+可以改善认知功能。此外，有证据表明，在临床前AD模型中， 因此，神经元对NAD+的损失加速，并且神经元特别容易受到细胞内NAD+水平降低的影响。 已经确定NAD补救途径中的限速酶是烟酰胺 磷酸核糖基转移酶（NAMPT）和NAMPT的酶活性在很大程度上决定了磷酸核糖基转移酶的水平。 细胞内的NAD+。在这里，我们描述了一个早期阶段的药物开发建议，以促进脑渗透剂， 小分子增强NAMPT活性，从而增加神经元NAD+水平和对抗大脑衰老。 我们描述了该分子的开发计划，直至IND申请阶段。最终的临床适应症 这样的分子将存在于患有LOAD和轻度认知障碍的患者中。我们召集了一个小组 在临床前和临床竞技场领域拥有丰富的药物开发和AD经验。这项建议 描述了一系列里程碑和进行/不进行决策点，以推进我们目前的三个不同的 化学系列，所有这些都直接与NAMPT结合并增加酶活性，以单一的最终临床 候选人将准备推进到人类受试者的I期测试。这种化合物将是第一个- 一类小分子，旨在逆转NAD+水平的年龄依赖性下降，作为治疗轻度 LOAD患者的认知障碍。

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.