Abstract

A series of benzylamino inhibitors of acetylcholinesterase (AChE) have been designed based on a working hypothesis of the enzymes 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 Alzheimers 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 Alzheimers disease. This article reviews design and structure-activity relationships of TAK-147 and related compounds. Preclinical pharmacology of TAK-147 is also summarized.

Keywords: central selective acetylcholinesterase inhibitor, TAK 147, neurotrophic activity, benzylamino inhibitors, acetylchoinesterase AChE, Phenylmethy 4 piperidinyl, tetrahydro 1H1 benzaazepin 8 yl propanone fumarate TAK147, NGF like neurotrophic activity, alzhemier s disease, tacrine THA, donepezil, rivastigmine, phthalimdie, docking analysis, torpedo californica, central selective inhibitors, pharmacokinetics, physostigmine, pharmacology, behavioral depression monoamine metabolism, amelioring effect, learning, memory impairment, ChAT activity Neurotrophic activity