title: Development of proneurogenic, neuroprotective small molecules.
abstract: Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apoptotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Karen S
authors.initials: KS
authors.lastname: MacMillan
authors.forename: Jacinth
authors.initials: J
authors.lastname: Naidoo
authors.forename: Jue
authors.initials: J
authors.lastname: Liang
authors.forename: Lisa
authors.initials: L
authors.lastname: Melito
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Lorraine
authors.initials: L
authors.lastname: Morlock
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Huntington
authors.forename: Sandi Jo
authors.initials: SJ
authors.lastname: Estill
authors.forename: Jamie
authors.initials: J
authors.lastname: Longgood
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Becker
authors.forename: Steven L
authors.initials: SL
authors.lastname: McKnight
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
authors.forename: Jef K
authors.initials: JK
authors.lastname: De Brabander
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ready
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004355:Drug Stability; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D055495:Neurogenesis / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D002227:Carbazoles; D018696:Neuroprotective Agents; C552520:P7C3 compound