9-Amino-1,2,3,4-tetrahydroacridin-1-ols: synthesis and evaluation as potential Alzheimer's disease therapeutics.
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 1 p showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC50 = 0.070 and 0.30 microM, 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.
Department of Chemical Research, Hoechst-Roussel Pharmaceuticals, Inc., Somerville, New Jersey 08876.
G M
GM
Shutske
F A
FA
Pierrat
K J
KJ
Kapples
M L
ML
Cornfeldt
M R
MR
Szewczak
F P
FP
Huger
G M
GM
Bores
V
V
Haroutunian
K L
KL
Davis
D000544:Alzheimer Disease / Q000188:drug therapy*; D000609:Aminoacridines / Q000138:chemical synthesis*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000633:toxicity; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D012601:Scopolamine / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity
D000609:Aminoacridines; D002800:Cholinesterase Inhibitors; D013619:Tacrine; D012601:Scopolamine