Neuroprotective Small Molecules as Novel Treatments for ALS

肌萎缩侧索硬化症(ALS)是一种毁灭性的和迅速致命的神经退行性疾病，涉及 控制肌肉随意运动的上、下运动神经元死亡。目前肌萎缩侧索硬化症的患病率 据估计，美国有2万人，每年约有5000例新病例。尽管所有种族的人和 不同种族的人同样容易患上肌萎缩侧索硬化症，退伍军人患这种疾病的频率比 普通人口。男性也比女性更容易受到影响。尽管肌萎缩侧索硬化症是多因素的 随着运动神经元的死亡，疾病的起源、进展和严重程度统一推进。因此，预计 阻止运动神经元死亡的神经保护剂可能为患者提供新的治疗选择。 然而，目前还没有药物可以阻止ALS或任何其他形式的神经细胞死亡。 神经退行性变。在这里，我们寻求提高P7C3-Class的效力、疗效和安全性 我们已经开发的神经保护分子，希望能解决这一未得到满足的需求。我们有 先前研究表明，P7C3-A20，一种P7C3的高活性类似物，可以延缓运动神经元的死亡和丢失 肌萎缩侧索硬化症临床前模型G93A-SOD1转基因小鼠的运动功能我们现在建议评估 我们进化最快的P7C3类似物(-)-P7C3-S243的有效性，它已在 帕金森氏病和冲击波介导的创伤性脑损伤(TBI)的严格临床前模型。多数 值得注意的是，轴突变性是ALS的一个显著特征，(-)-P7C3-S243专门阻止损伤- 在这个脑损伤模型中，在没有神经元胞体死亡的情况下，诱导了轴突变性。我们已经做出了 在药物化学方面取得了实质性进展，(-)-P7C3-S243缺乏原始P7C3的苯胺部分 没有明显的毒性，包括对人的HERG通道没有抑制作用。此外， 在啮齿动物中，长期服用(-)-P7C3-S243的剂量是 是治疗效果所必需的。重要的是，我们最近还确定了P7C3的分子靶点 烟酰胺磷酸核糖转移酶(NAMPT)等分子。NAMPT催化了限速步骤 烟酰胺腺嘌呤二核苷酸(NAD)回收，以及P7C3的活性类似物增强其对 在活细胞中将烟酰胺转化为烟酰胺单核苷酸(NMN)和NAD。强有力的历史证据表明 Long预测，能够提高NAD水平的药物在治疗糖尿病方面应该是唯一有益的 神经退行性疾病。除了机械洞察力之外，了解P7C3的分子靶标还可以 美国将探索比以前允许的更广泛的化学领域。新分子的功效首先将是 通过体外活性测试进行评估，然后对成功的先导进行体外和体内评估 药代动力学特性。通过这些标准的分子将随后在体内测试中进行评估。 海马神经保护，我们最初的筛选平台，确定了P7C3分子。最后， 表现与我们目前最有希望的线索一样好或更好的分子将受到 在两种ALS动物模型(G93A-SOD1小鼠和ChAT-TTA-9/TDP-43M337V大鼠)上进行了严格的测试， 结果测量包括运动功能和神经元存活。这些产品的防护功效 模型将与大脑和脊髓中化合物的中枢神经系统水平相关。我们的目标是前进 我们的科学从临床前环境到人类第一次临床测试一种治疗ALS的神经保护药物。

Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly fatal neurodegenerative disease involving death of upper and lower motor neurons controlling voluntary muscle movement. Current prevalence of ALS in the U.S. is estimated at 20,000, with about 5,000 new cases per year. Though people of all races and ethnicities are equally susceptible to ALS, this disease strikes military veterans more frequently than the general population. Men are also more frequently affected than women. Although ALS is multi-factorial in origin, disease progression and severity uniformly advance as motor neurons die. It is thus expected that neuroprotective agents that block motor neuron death might provide new therapeutic options for patients. However, there are no drugs available that block neuronal cell death, in ALS or any other form of neurodegeneration. Here, we seek to improve the potency, efficacy and safety of the P7C3-class of neuroprotective molecules that we have developed, in hopes of addressing this unmet need. We have previously shown that P7C3-A20, a highly active analog of P7C3, delays motor neuron cell death and loss of motor function in G93A-SOD1 transgenic mice, a preclinical model of ALS. We now propose to evaluate the efficacy of our most highly evolved analogue of P7C3, known as (-)-P7C3-S243, which has shown efficacy in rigorous preclinical models of Parkinson’s disease and blast-mediated traumatic brain injury (TBI). Most notably, axonal degeneration is a prominent feature of ALS, and (-)-P7C3-S243 specifically blocks injury- induced axonal degeneration in the absence of neuron cell body death in this model of TBI. We have made substantial progress in medicinal chemistry, and (-)-P7C3-S243 lacks the aniline moiety of the original P7C3 chemical and shows no overt toxicity, including no inhibition of the human hERG channel. Furthermore, prolonged administration of (-)-P7C3-S243 is well tolerated in rodents at doses 10- to 30-fold higher than required for therapeutic efficacy. Importantly, we have also recently identified the molecular target of the P7C3 molecules as nicotinamide phosphoribosyltransferase (NAMPT). NAMPT catalyzes the rate-limiting step in nicotinamide adenine dinucleotide (NAD) salvage, and active analogues of P7C3 enhance its conversion of nicotinamide into nicotinamide mononucleotide (NMN) and NAD in living cells. Strong historical evidence has long predicted that drugs capable of enhancing NAD levels should be uniquely beneficial in treatment of neurodegenerative disease. In addition to mechanistic insight, knowing the molecular target of P7C3 enables us to explore wider swaths of chemistry than previously allowed. Efficacy of new molecules will first be evaluated by in vitro assays of activity, and successful leads will then be evaluated for in vitro and in vivo pharmacokinetic properties. Molecules passing these criteria will be subsequently evaluated in in vivo assays of hippocampal neuroprotection, our original screening platform that identified the P7C3 molecule. Finally, molecules that perform as well or better than our current most promising leads will then be subjected to rigorous testing in two animal models of ALS (G93A-SOD1 mice and ChAT-tTA-9/TDP-43M337V rats), with outcome measures encompassing both motor function and neuronal survival. Protective efficacy in these models will be correlated with CNS levels of the compounds in brain and spinal cord. Our goal is to advance our science from a pre-clinical setting towards first-in-human clinical testing of a neuroprotective drug for ALS.