title: P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases.
abstract: 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.
authors: Departments of Psychiatry, Neurology, and Veterans Affairs, University of Iowa Carver College of Medicine, 200 Hawkins Ave, Iowa City, IA 52242, USA.
authors: Andrew A
authors: AA
authors: Pieper
authors: Steven L
authors: SL
authors: McKnight
authors: Joseph M
authors: JM
authors: Ready
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D002227:Carbazoles; D018696:Neuroprotective Agents; C552520:P7C3 compound