A series of benzylamino inhibitors of
acetylcholinesterase (AChE) have been designed based on a working hypothesis of the
enzyme s active site. These compounds were tested for their inhibitory activities on AChE and potent inhibitors were further evaluated in terms of central selectivity. These studies led to a discovery of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4, 5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone
fumarate (TAK-147). Pharmacokinetic study has shown that the compound has high central selectivity, as demonstrated by rapid elimination from plasma and long-term existence in the brain. As a consequence,
TAK-147 ameliorates impairments of learning and memory in various animal models without producing peripheral side effects.
TAK-147 also activates the monoaminergic systems and energy metabolism. Furthermore,
TAK-147 was revealed to have
NGF-like neurotrophic activity on central cholinergic neurons at concentrations where it inhibits AChE activity. Therefore,
TAK-147 is expected not only to ameliorate the clinical symptoms in
Alzheimer s disease via AChE inhibition but to prevent or slow the progression of the disease via its neurotrophic action.
TAK-147 is now under clinical trial as a therapeutic
drug for
Alzheimer s disease. This article reviews design and structure-activity relationships of
TAK-147 and related compounds. Preclinical pharmacology of
TAK-147 is also summarized.