Small Molecule Modulators of the Glutamate Transporter for Treatment of ALS

谷氨酸转运蛋白小分子调节剂治疗 ALS

• 批准号: 8294684
• 负责人: Gregory D Cuny
• 金额: $ 3.89万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294684
• 关键词: Acute; Amyotrophic Lateral Sclerosis; Astrocytes; Brain; Brain Stem; Carrier Proteins; Cell Line; Chronic; Collaborations; Diagnosis; Disease; Dose; Drug Kinetics; Glutamate Transporter; Glutamates; Goals; Grant; Lead; Life Expectancy; Maximum Tolerated Dose; Motor Cortex; Mus; Neurodegenerative Disorders; Ohio; Pharmaceutical Chemistry; Property; Spinal Cord; Time; United States; Universities; excitotoxicity; improved; in vivo; motor neuron degeneration; novel therapeutics; protein expression; small molecule

DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS), also called Lou Gehrig's disease in the United States, is a late-onset, devastating fatal neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the spinal cord, motor cortex and brainstem. The goal of this U01 Blueprint grant is to optimize and develop small molecule activators of EAAT2 glutamate transporter protein expression as a means to treat ALS. EAAT2 expression is highly regulated at the translational level. In collaboration that was started more than 3 years ago with Dr. Lin at Ohio State University, we have identified molecules that increase expression of EAAT2 through a translational mechanism. Increased EAAT2 expression has been shown to compensate for the excessive excitotoxicity from high glutamate levels found in a number of diseases including ALS. The two lead molecules have been shown to cause a dose and time dependent increase in EAAT2 in a primary astrocyte cell line and in mouse spinal cord and brain. These compounds have been optimized to demonstrate proof-of-concept in vivo, but still need to be further optimized to improve potency and pharmacokinetic properties. Pharmacokinetic studies have been completed and acute and chronic maximum tolerated dose studies are in progress to help drive additional medicinal chemistry efforts.

描述（由申请人提供）：肌萎缩性外侧硬化症（ALS），也称为美国的Lou Gehrig病，是一种晚期发作的，毁灭性的致命神经退行性疾病，其特征在于脊髓，运动皮质和脑系统中运动神经元的逐步退化。该U01蓝图赠款的目的是优化和开发EAAT2谷氨酸转运蛋白表达的小分子激活剂，作为治疗ALS的一种手段。 EAAT2表达在翻译水平上受到高度调节。在3年前与俄亥俄州立大学Lin博士启动的合作中，我们已经确定了通过翻译机制增加EAAT2表达的分子。已显示EAAT2表达增加可补偿来自包括ALS在内的多种疾病中发现的高谷氨酸水平的过度兴奋性。已显示这两个铅分子在原代星形细胞系以及小鼠脊髓和脑中引起EAAT2的剂量和时间依赖性增加。这些化合物已被优化以证明体内的概念验证，但仍需要进一步优化以提高效力和药代动力学特性。药代动力学研究已经完成，急性和慢性最大耐受剂量研究正在进行中，以帮助推动其他药物化学努力。