TY - JOUR
T1 - 9-amino-l,2,3,4-tetrahydroacridin-l-ols
T2 - Synthesis and Evaluation As Potential Alzheimer'S Disease Therapeutics
AU - Shutske, Gregory M.
AU - Pierrat, Frank A.
AU - Kapples, Kevin J.
AU - Cornfeldt, Michael L.
AU - Szewczak, Mark R.
AU - Huger, Francis P.
AU - Bores, Gina M.
AU - Haroutunian, Vahram
AU - Davis, Kenneth L.
PY - 1989/8/1
Y1 - 1989/8/1
N2 - The synthesis of a series of 9-amino-l,2,3,4-tetrahydroacridin-l-ols is reported. These compounds are related to l,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-l,2,3,4-tetrahydroacridin-l-ol maleate (la, HP-029) and (±)-9-(benzylamino)-l,2,3,4-tetrahydroacridin-l-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 lp showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC50 = 0.070 and 0.30 μM, respectively). Compounds la and lp, 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.
AB - The synthesis of a series of 9-amino-l,2,3,4-tetrahydroacridin-l-ols is reported. These compounds are related to l,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-l,2,3,4-tetrahydroacridin-l-ol maleate (la, HP-029) and (±)-9-(benzylamino)-l,2,3,4-tetrahydroacridin-l-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 lp showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC50 = 0.070 and 0.30 μM, respectively). Compounds la and lp, 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.
UR - http://www.scopus.com/inward/record.url?scp=0024336329&partnerID=8YFLogxK
U2 - 10.1021/jm00128a024
DO - 10.1021/jm00128a024
M3 - Article
C2 - 2754707
AN - SCOPUS:0024336329
SN - 0022-2623
VL - 32
SP - 1805
EP - 1813
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -