Vol. 280, Issue 2, 710-720, 1997

Pharmacological Activity and Safety Profile of P10358, a Novel, Orally Active Acetylcholinesterase Inhibitor for Alzheimer's Disease

Craig P. Smith, Gina M. Bores, Wayne Petko, Mary Li, David E. Selk, Douglas K. Rush, Fernando Camacho, James T. Winslow, Rod Fishkin, Dana M. Cunningham, Karen M. Brooks, Joachim Roehr, Harold B. Hartman, Larry Davis and Hugo M. Vargas

Hoechst Marion Roussel, Inc., Neuroscience Therapeutic Domain, Bridgewater, New Jersey

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 µM vs. IC₅₀ = 0.25 ± 0.03 µM). It also inhibits butyrylcholinesterase activity as potently as THA (IC₅₀ = 0.08 ± 0.05 µM vs. IC₅₀ = 0.07 ± 0.01 µM). 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 µM) 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.