Neuroprotective Small Molecules as Novel Treatments for ALS

描述(由申请人提供)： 肌萎缩侧索硬化症(ALS)是一种毁灭性的、迅速致死的神经退行性疾病，涉及控制随意肌肉运动的上下运动神经元的死亡。目前美国ALS的患病率估计为20,000人，每年约有5,000例新病例。尽管所有种族和民族的人都同样容易患上肌萎缩侧索硬化症，但退伍军人比普通民众更容易患上这种疾病。男性也比女性更容易受到影响。虽然肌萎缩侧索硬化症的起源是多因素的，但随着运动神经元的死亡，疾病的进展和严重程度一致地发展。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退行性变中的神经细胞死亡。在这里，我们寻求提高我们开发的P7C3类神经保护分子的效力、有效性和安全性，希望解决这一未得到满足的需求。我们之前已经证明，P7C3-A20，一种P7C3的高活性类似物，可以延缓G93A-SOD1转基因小鼠的运动神经元细胞死亡和运动功能的丧失，G93A-SOD1转基因小鼠是ALS的临床前模型。我们现在建议评估我们进化最快的P7C3类似物，即(-)-P7C3-S243，它已在严格的帕金森病和冲击波介导的创伤性脑损伤(TBI)临床前模型中显示出有效性。最值得注意的是，轴突变性是ALS的一个显著特征，在这种脑损伤模型中，(-)-P7C3-S243特异性地阻断了损伤诱导的轴突变性，而没有神经元胞体死亡。我们在药物化学方面取得了实质性进展，(-)-P7C3-S243缺乏原始P7C3化学物质的苯胺部分，也没有明显的毒性，包括对人类Herg通道的抑制。此外，在啮齿动物中，长期服用(-)-P7C3-S243的剂量是治疗效果所需剂量的10到30倍，耐受性很好。重要的是，我们最近还确定了P7C3分子的分子靶点是烟酰胺磷酸核糖转移酶(NAMPT)。NAMPT催化烟酰胺腺嘌呤二核苷酸(NAD)回收的限速步骤，P7C3的活性类似物在活细胞中促进其转化为烟酰胺单核苷酸(NMN)和NAD。强有力的历史证据长期以来一直预测，能够提高NAD水平的药物在治疗神经退行性疾病方面应该是唯一有益的。除了机械上的洞察外，了解P7C3的分子靶点使我们能够探索比以前允许的更广泛的化学领域。新分子的有效性将首先通过体外活性测试进行评估，然后将评估成功的先导化合物在体外和体内的药代动力学特性。通过这些标准的分子随后将在海马神经保护的体内分析中进行评估，这是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在两个ALS动物模型(G93A-SOD1小鼠和Chat-TTA-9/TDP-43M337V大鼠)中接受严格测试，结果指标包括运动功能和神经元存活。这些模型的保护效果将与大脑和脊髓中化合物的中枢神经系统水平相关。我们的目标是推动我们的科学从临床前环境走向人类第一次临床测试一种治疗ALS的神经保护性药物。

DESCRIPTION (provided by applicant): 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.