Pieper Andrew A, McKnight Steven L, Ready Joseph M
Departments of Psychiatry, Neurology, and Veterans Affairs, University of Iowa Carver College of Medicine, 200 Hawkins Ave, Iowa City, IA 52242, USA.
Chem Soc Rev. 2014 Oct 7;43(19):6716-26. doi: 10.1039/c3cs60448a.
A novel neuroprotective small molecule was discovered using a target-agnostic in vivo screen in living mice. This aminopropyl carbazole, named P7C3, is orally bioavailable, crosses the blood-brain barrier, and is non-toxic at doses several fold higher than the efficacious dose. The potency and drug-like properties of P7C3 were optimized through a medicinal chemistry campaign, providing analogues for detailed examination. Improved versions, such as (-)-P7C3-S243 and P7C3-A20, displayed neuroprotective properties in rodent models of Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury and age-related cognitive decline. Derivatives appended with immobilizing moieties may reveal the protein targets of the P7C3 class of neuroprotective compounds. Our results indicate that unbiased, in vivo screens might provide starting points for the development of treatments for neurodegenerative diseases as well as tools to study the biology underlying these disorders.
通过在活体小鼠中进行的无靶点体内筛选，发现了一种新型神经保护小分子。这种氨丙基咔唑名为P7C3，口服具有生物利用度，可穿过血脑屏障，并且在比有效剂量高几倍的剂量下无毒。通过药物化学研究优化了P7C3的效力和类药物性质，提供了用于详细研究的类似物。改进版本，如(-)-P7C3-S243和P7C3-A20，在帕金森病、肌萎缩侧索硬化症、创伤性脑损伤和年龄相关性认知衰退的啮齿动物模型中显示出神经保护特性。带有固定基团的衍生物可能会揭示P7C3类神经保护化合物的蛋白质靶点。我们的结果表明，无偏倚的体内筛选可能为神经退行性疾病治疗的开发提供起点，以及研究这些疾病背后生物学的工具。
