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: 10057083
• 负责人: ANDREW A PIEPER
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND 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/10057083
• 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; research clinical testing; scaffold; screening; small molecule; superoxide dismutase 1

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.

肌萎缩侧索硬化症（ALS）是一种破坏性和迅速致命的神经退行性疾病， 控制随意肌肉运动的上下运动神经元死亡。ALS的当前患病率 美国估计有20，000例，每年约有5，000例新病例。虽然所有种族的人， 种族同样容易患ALS，这种疾病比退伍军人更频繁地袭击退伍军人。 一般人口。男性也比女性更经常受到影响。虽然ALS是多因素的， 起源、疾病进展和严重程度随着运动神经元死亡而一致地进展。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或任何其他形式的肌萎缩性侧索硬化症中，没有药物可用于阻断神经元细胞死亡。 神经变性在此，我们寻求提高P7 C3类药物的效力、功效和安全性。 我们开发的神经保护分子，希望能解决这个未满足的需求。我们有 先前的研究表明，P7 C3-A20，一种高活性的P7 C3类似物，可以延迟运动神经元细胞的死亡和细胞凋亡的丧失。 G93 A-SOD 1转基因小鼠的运动功能，ALS的临床前模型。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，其在以下方面显示出功效： 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。最 值得注意的是，轴突变性是ALS的显著特征，并且（-）-P7 C3-S243特异性地阻断损伤， 在该TBI模型中，在没有神经元细胞体死亡的情况下诱导轴突变性。我们取得了 在药物化学上的实质性进展，并且（-）-P7 C3-S243缺少原始P7 C3的苯胺部分 化学品，并显示没有明显的毒性，包括没有抑制人类hERG通道。此外，委员会认为， 在啮齿类动物中，以高于（-）-P7 C3-S243的10- 30倍的剂量长期施用（-）-P7 C3-S243是良好耐受的。 治疗效果所需的。重要的是，我们最近还确定了P7 C3的分子靶点， 烟酰胺磷酸核糖基转移酶（NAMPT）。NAMPT催化的限速步骤， 烟酰胺腺嘌呤二核苷酸（NAD）补救和P7 C3的活性类似物增强其转化， 在活细胞中，烟酰胺转化为烟酰胺单核苷酸（NMN）和NAD。有力的历史证据表明， 长期预测，能够提高NAD水平的药物应该是唯一有益的治疗， 神经退行性疾病除了机理上的见解，了解P7 C3的分子靶点， 让我们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，然后对成功的电极导线进行体外和体内评价。 药代动力学特性通过这些标准的分子随后将在体内测定中进行评价 海马神经保护，我们最初的筛选平台，确定P7 C3分子。最后， 然后，与我们目前最有前途的先导化合物一样或更好地发挥作用的分子将受到 在两种ALS动物模型（G93 A-SOD 1小鼠和ChAT-tTA-9/TDP-43 M337 V大鼠）中进行了严格的测试， 结果测量包括运动功能和神经元存活。保护功效在这些 模型将与脑和脊髓中化合物的CNS水平相关。我们的目标是 我们的科学从临床前的设置走向首次在人体临床测试的神经保护药物的ALS。

项目成果

2-(2,5-Di-meth-oxy-phen-yl)-4,5-diphenyl-1-(prop-2-en-1-yl)-1H-imidazole.

2-(2,5-二甲氧基-苯基)-4,5-二苯基-1-(丙-2-烯-1-基)-1H-咪唑。

• DOI: 10.1107/s1600536813015936
• 发表时间: 2013
• 期刊: Acta crystallographica. Section E, Structure reports online
• 作者: Akkurt,Mehmet;Mohamed,ShaabanK;Marzouk,AdelA;Abdelhamid,AntarA;Santoyo-Gonzalez,Francisco
• 通讯作者: Santoyo-Gonzalez,Francisco