Neuroprotective Small Molecules as Novel Treatments for ALS

神经保护小分子作为 ALS 的新型治疗方法

• 批准号: 10002159
• 负责人: ANDREW A PIEPER
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002159
• 关键词: Address; Adenine; Affect; Amyotrophic Lateral Sclerosis; Aniline; Animal Model; Biochemical; Biological Assay; Biological Availability; Blood; Brain; Carbazoles; Cells; Cessation of life; Characteristics; Chemicals; Chemistry; Collaborations; Development; Disease; Disease Progression; Dose; Doxorubicin; Drug Kinetics; Drug toxicity; Enzyme Activators; Enzymes; Ethnic Origin; General Population; Genetic study; Goals; Hippocampus (Brain); Human; In Vitro; Injury; Laboratories; Lead; Mediating; Medical center; Military Personnel; Modeling; Molecular Target; Motor; Motor Neurons; Movement; Mus; Mutant Strains Mice; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Oral; Outcome Measure; Parkinson Disease; Pathogenicity; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pre-Clinical Model; Prevalence; Process; Property; Race; Rattus; Research; Resources; Rodent; Rodent Model; Safety; Science; Series; Severity of illness; Skeletal Muscle; Solubility; Spinal Cord; System; Testing; Texas; Toxic effect; Toxicology; Transgenic Animals; Transgenic Mice; Traumatic Brain Injury; Treatment Efficacy; Universities; Variant; Veterans; Woman; analog; axonal degeneration; base; design; dimer; efficacy testing; first-in-human; improved; in vitro Assay; in vitro testing; in vivo; insight; meetings; member; men; mutant; neuron loss; neuronal survival; neuroprotection; nicotinamide phosphoribosyltransferase; novel; novel therapeutics; pre-clinical; preclinical development; preservation; professor; protective efficacy; public health relevance; research clinical testing; scaffold; screening; small molecule; superoxide dismutase 1

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.

描述（由申请人提供）： 肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种破坏性的、迅速致命的神经退行性疾病，它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，每年约有5，000例新发病例。尽管所有种族和民族的人都同样容易患肌萎缩侧索硬化症，但这种疾病对退伍军人的影响比普通人群更频繁。男性也比女性更经常受到影响。虽然ALS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进展。因此，预期阻断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，在ALS或任何其他形式的神经变性中，没有药物可以阻止神经元细胞死亡。在这里，我们寻求提高我们开发的P7 C3类神经保护分子的效力、功效和安全性，希望解决这一未满足的需求。我们先前已经证明，P7 C3-A20，一种高度活性的P7 C3类似物，在G93 A-SOD 1转基因小鼠（ALS的临床前模型）中延迟运动神经元细胞死亡和运动功能丧失。我们现在建议评估我们最高度进化的P7 C3类似物（称为（-）-P7 C3-S243）的疗效，该类似物已在帕金森病和爆炸介导的创伤性脑损伤（TBI）的严格临床前模型中显示出疗效。最值得注意的是，轴突变性是ALS的显著特征，并且在该TBI模型中，在不存在神经元细胞体死亡的情况下，（-）-P7 C3-S243特异性地阻断损伤诱导的轴突变性。我们在药物化学方面取得了实质性进展，（-）-P7 C3-S243缺乏原始P7 C3化学品的苯胺部分，并且没有显示出明显的毒性，包括对人hERG通道没有抑制作用。此外，在啮齿动物中，以比治疗功效所需的剂量高10至30倍的剂量长期施用（-）-P7 C3-S243是良好耐受的。重要的是，我们最近还鉴定了P7 C3分子的分子靶标为烟酰胺磷酸核糖基转移酶（NAMPT）。NAMPT催化烟酰胺腺嘌呤二核苷酸（NAD）补救中的限速步骤，P7 C3的活性类似物增强其在活细胞中将烟酰胺转化为烟酰胺单核苷酸（NMN）和NAD。强有力的历史证据早就预测，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独特有益的。除了机理上的洞察力，了解P7 C3的分子靶点使我们能够探索比以前更广泛的化学领域。新分子的功效将首先通过体外活性测定进行评价，然后将评价成功的先导化合物的体外和体内药代动力学特性。通过这些标准的分子随后将在海马神经保护的体内测定中进行评估，海马神经保护是我们鉴定P7 C3分子的原始筛选平台。最后，与我们目前最有前途的先导化合物一样好或更好的分子将在两种ALS动物模型（G93 A-SOD 1小鼠和ChAT-tTA-9/TDP-43 M337 V大鼠）中进行严格的测试，结果指标包括运动功能和神经元存活。这些模型中的保护功效将与脑和脊髓中化合物的CNS水平相关。我们的目标是将我们的科学从临床前环境推进到ALS神经保护药物的首次人体临床试验。