Journal of Medicinal Chemistry p. 2292 - 2299 (1994)
Update date:2022-08-05
Topics:
Ishihara, Yuji
Hirai, Keisuke
Miyamoto, Masaomi
Goto, Giichi
In an attempt to find central selective acetylcholinesterase (AChE) inhibitors, 3-<1-(phenylmethyl)-4-piperidinyl>-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanones 9 and their analogs were designed on the basis of our working hypothesis of the enzyme's active site.These compounds were prepared by regioselective Fridel-Crafts acylation of 2,3,4,5-tetrahydro-1H-1-benzazepines and related nitrogen heterocycles as a key step.Most compounds showed potent inhibitory activities with IC50s in the 10-300 nM range.In order to estimate their central selectivities, we examined their effects on the apomorphine-induced circling behavior in rats with unilateral striatal lesions.Among compounds with potent AChE inhibition, 3-<1-(phenylmethyl)-4-piperidinyl>-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (9a, TAK-147) (IC50 of AChE inhibition = 97.7 nM) inhibited the circling behavior at 3 mg/kg po, in which it had no significant effect on peripheral cholinergic effects.This demonstrates that 9a has favorable central selectivity.Furthermore, 9a significantly ameliorated diazepam-induced passive avoidance deficit at 1 mg/kg po.The benzazepine derivative 9a was selected as a candidate for clinical evaluation.
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