9-Amino-1,2,3,4-tetrahydroacridin-1-ols: Synthesis and evaluation as potential Alzheimer's disease therapeutics

Article abstract of DOI:10.1021/jm00128a024

The synthesis of a series of 9-amino-1,2,3,4-tetrahydroacridin-1-ols is reported. These compounds are related to 1,2,3,4-tetrahydro-9-acridinamine (THA, tacrine). They inhibit acetylcholinesterase in vitro and are active in a model that may be predictive of activity in Alzheimer's disease - the scopolamine-induced impairment of 24-h memory of a passive dark-avoidance paradigm in mice. Two compounds, (±)-9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate (1a, HP-029) and (±)-9-(benzylamino)-1,2,3,4-tetrahydroacridin-1-ol maleate (1p, HP-128), were also active in reversing the deficit in 72-h retention of a one-trial dark-avoidance task in rats, induced by ibotenic acid lesions in the nucleus basalis magnocellularis. In addition, compound 1p showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC₅₀ = 0.070 and 0.30 μM, respectively). Compounds 1a and 1p, which showed less acute toxicity in both rats and mice than THA, are in phase II and phase I clinical trials, respectively, for Alzheimer's disease.