Discovery of a neuroprotective chemical, (S)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(-)-P7C3-S243], with improved druglike properties.
(-)-P7C3-S243 is a neuroprotective aminopropyl carbazole with improved druglike properties compared with previously reported compounds in the P7C3 class. It protects developing neurons in a mouse model of hippocampal neurogenesis and protects mature neurons within the substantia nigra in a mouse model of Parkinson's disease. A short, enantioselective synthesis provides the neuroprotective agent in optically pure form. It is nontoxic, orally bioavailable, metabolically stable, and able to cross the blood-brain barrier. As such, it represents a valuable lead compound for the development of drugs to treat neurodegenerative diseases and traumatic brain injury.
Departments of †Biochemistry and ‡Neuroscience, University of Texas Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
Jacinth
J
Naidoo
Hector
H
De Jesus-Cortes
Paula
P
Huntington
Sandi
S
Estill
Lorraine K
LK
Morlock
Ruth
R
Starwalt
Thomas J
TJ
Mangano
Noelle S
NS
Williams
Andrew A
AA
Pieper
Joseph M
JM
Ready
D000818:Animals; D019540:Area Under Curve; D002227:Carbazoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D055808:Drug Discovery; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D010300:Parkinson Disease / Q000473:pathology; D021241:Spectrometry, Mass, Electrospray Ionization; D013378:Substantia Nigra / Q000473:pathology
D002227:Carbazoles; D018696:Neuroprotective Agents; C552520:P7C3 compound