Central selective acetylcholinesterase inhibitor with neurotrophic activity: structure-activity relationships of TAK-147 and related compounds.
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.
Ishihara
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Medicinal Chemistry Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawaku, Osaka, 532-8686, Japan. Ishihara_Yuji@takeda.co.jp
Goto
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Miyamoto
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D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D000882:Haplorhini; D006801:Humans; D010797:Phthalimides / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
D001552:Benzazepines; D002800:Cholinesterase Inhibitors; D010797:Phthalimides; C099872:TAK 147; D002795:Choline O-Acetyltransferase