Small Molecule Modulators of the Glutamate Transporter for Treatment of ALS

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS），在美国也称为Lou Gehrig's病，是一种迟发性、毁灭性的致命神经退行性疾病，其特征是脊髓、运动皮层和脑干的运动神经元进行性变性。U01 Blueprint资助的目标是优化和开发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的表达在翻译水平上受到高度调控。在三年多前与俄亥俄州立大学的林博士的合作中，我们已经确定了通过翻译机制增加EAAT2表达的分子。EAAT2表达的增加已被证明可以补偿在包括ALS在内的许多疾病中发现的高谷氨酸水平引起的过度兴奋毒性。这两种先导分子已被证明能引起原代星形胶质细胞系和小鼠脊髓和大脑中EAAT2的剂量和时间依赖性增加。这些化合物已经过优化以在体内进行概念验证，但仍需要进一步优化以提高效力和药代动力学性质。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，以帮助推动更多的药物化学工作。

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.