title: Pharmacological activity and safety profile of P10358, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease.
abstract: 1-[(3-Fluoro-4-pyridinyl)amino]-3-methyl-1(H)-indol-5-yl methyl carbamate (P10358) is a potent, reversible acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral and parental administration in rats and mice. P10358 is a 2.5 times more potent acetylcholinesterase inhibitor than THA in vitro (IC50 = 0.10 +/- 0.02 microM vs. IC50 = 0.25 +/- 0.03 microM). It also inhibits butyrylcholinesterase activity as potently as THA (IC50 = 0.08 +/- 0.05 microM vs. IC50 = 0.07 +/- 0.01 microM). Ex vivo, P10358 (0.2 - 20 mg/kg, p.o.) produced dose-dependent inhibition of brain acetylcholinesterase activity. At 10 and 20 mg/ kg, it produced profound and long-lasting hypothermia in mice. P10358 enhanced performance in rats in a step-down passive avoidance task (0.62 and 1.25 mg/kg) and in a social recognition paradigm (0.32, 0.64 and 1.25 mg/kg) in mice. It reversed scopolamine-induced deficits in the Morris Water maze in rats (1.25 and 2.5 mg/kg) and a higher dose elevated striatal homovanillic acid levels. These behavioral and biochemical effects are consistent with central cholinergic stimulation. Hemodynamic studies in the rat demonstrated a 16-fold separation between behaviorally active doses (1.25 mg/kg) and those that elevated arterial pressure (20 mg/kg). Lethality in rats occurred at an oral dose of 80 mg/kg, but not at lower doses. Chemically, P10358 is an N-aminoindole and may not have the hepatotoxic liability associated with aminoacridine structure of tacrine. P10358 had weak affinity (>10 microM) at a variety of aminergic and peptidergic receptors and uptake carriers. These properties suggest that P10358 may be a safe and promising symptomatic treatment for Alzheimer's disease.
authors.affiliation: Hoechst Marion Roussel, Inc., Neuroscience Therapeutic Domain, Bridgewater, New Jersey 08807-0800, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Smith
authors.forename: G M
authors.initials: GM
authors.lastname: Bores
authors.forename: W
authors.initials: W
authors.lastname: Petko
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: D E
authors.initials: DE
authors.lastname: Selk
authors.forename: D K
authors.initials: DK
authors.lastname: Rush
authors.forename: F
authors.initials: F
authors.lastname: Camacho
authors.forename: J T
authors.initials: JT
authors.lastname: Winslow
authors.forename: R
authors.initials: R
authors.lastname: Fishkin
authors.forename: D M
authors.initials: DM
authors.lastname: Cunningham
authors.forename: K M
authors.initials: KM
authors.lastname: Brooks
authors.forename: J
authors.initials: J
authors.lastname: Roehr
authors.forename: H B
authors.initials: HB
authors.lastname: Hartman
authors.forename: L
authors.initials: L
authors.lastname: Davis
authors.forename: H M
authors.initials: HM
authors.lastname: Vargas
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy; D000631:Aminopyridines / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002219:Carbamates / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D007036:Hypothermia, Induced; D007700:Kinetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory; D051379:Mice; D008815:Mice, Inbred Strains; D010052:Ovariectomy; D016548:Prosencephalon / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000494:pharmacology; D012919:Social Behavior; D013028:Space Perception; D013997:Time Factors
chemical_list: D000631:Aminopyridines; D002219:Carbamates; D002800:Cholinesterase Inhibitors; C104415:P 10358; D012601:Scopolamine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D004298:Dopamine