Preclinical Pharmacology of TAK‐147, a Novel Acetylcholinesterase Inhibitor, as a Potential Therapeutic Drug for Alzheimer's Disease

Miyamoto, Masaomi; Goto, Giichi

doi:10.1111/j.1527-3458.1997.tb00330.x

Cited by 3 publications

(6 citation statements)

References 79 publications

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“…Plasma and brain levels of TAK-147 after oral administration of 3 mg/kg of [ 14 C] TAK-147 to rats and monkeys are shown in Fig. (7 ) [26]. The plasma concentration rapidly decreased in both rats and monkeys, and half-lives (T 1/2 ) were 2.1 and 2.3 h, respectively.…”

Section: Behavior In Ratsmentioning

confidence: 95%

“…Repeated administration of TAK-147 (0.3 -3 mg/kg po) also decreased learning impairment in BFlesioned rats [26].…”

Section: Amelioratingmentioning

confidence: 97%

“…It has been generally shown that cholinergic stimulants induce sedation or behavioral depression, and these effects of AChE inhibitors may exacerbate depressive syndromes and weaken the ameliorating effects on the cognitive deficits in AD [31]. TAK-147 (2 -10 mg/kg po) has shown no depressive properties in the forced swimming test; in contrast, tacrine exacerbated the behavioral depression [26]. Treatment with TAK-147 (1 -10 mg/kg po) antagonized the reserpine-induced hypothermia and ptosis in a dose-dependent manner [29].…”

Section: Behavior In Ratsmentioning

confidence: 99%

“…The plasma concentration rapidly decreased in both rats and monkeys, and half-lives (T 1/2 ) were 2.1 and 2.3 h, respectively. The bioavailabilities of TAK-147 in rats The effects of TAK-147 on general behavior in rats were observed in detail [26]. TAK-147 produced miosis and fasciculation at relatively low doses; ED 50 s were 5 -10 mg/kg po.…”

Section: Behavior In Ratsmentioning

confidence: 99%

“…Effects of repeated administration of AChE inhibitors on the water maze learning deficit in aged rats were examined (Fig. (8 )) [26]. TAK-147 (0.1 and 1 mg/kg po) ameliorated impairments of learning and memory in aged rats, and marked effect was observed at 1 mg/kg.…”

Section: Amelioratingmentioning

confidence: 99%

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Central Selective Acetylcholinesterase Inhibitor with Neurotrophic Activity Structure-Activity Relationships of TAK-147 and Related Compounds

Ishihara¹,

Goto²,

Miyamoto³

2000

Current Medicinal Chemistry

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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.

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Section: Behavior In Ratsmentioning

confidence: 95%

“…Repeated administration of TAK-147 (0.3 -3 mg/kg po) also decreased learning impairment in BFlesioned rats [26].…”

Section: Amelioratingmentioning

confidence: 97%

Section: Behavior In Ratsmentioning

confidence: 99%

Section: Behavior In Ratsmentioning

confidence: 99%

Section: Amelioratingmentioning

confidence: 99%

See 3 more Smart Citations

Central Selective Acetylcholinesterase Inhibitor with Neurotrophic Activity Structure-Activity Relationships of TAK-147 and Related Compounds

Ishihara¹,

Goto²,

Miyamoto³

2000

Current Medicinal Chemistry

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N‐Benzyl piperidine Fragment in Drug Discovery

Sharma,

Bharate

2024

ChemMedChem

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The N‐benzyl piperidine (N‐BP) structural motif is commonly employed in drug discovery due to its structural flexibility and three‐dimensional nature. Medicinal chemists frequently utilize the N‐BP motif as a versatile tool to fine‐tune both efficacy and physicochemical properties in drug development. It provides crucial cation‐π interactions with the target protein and also serves as a platform for optimizing stereochemical aspects of potency and toxicity. This motif is found in numerous approved drugs and clinical/preclinical candidates. This review focuses on the applications of the N‐BP motif in drug discovery campaigns, emphasizing its role in imparting medicinally relevant properties. We provide an overview of approved drugs, the clinical and preclinical pipeline, and discuss its utility for specific therapeutic targets and indications, along with potential challenges.

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Combination of a novel antidementia drug FK960 with donepezil synergistically improves memory deficits in rats

Tokita

2002

Pharmacology Biochemistry and Behavior

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Preclinical Pharmacology of TAK‐147, a Novel Acetylcholinesterase Inhibitor, as a Potential Therapeutic Drug for Alzheimer's Disease

Cited by 3 publications

References 79 publications

Central Selective Acetylcholinesterase Inhibitor with Neurotrophic Activity Structure-Activity Relationships of TAK-147 and Related Compounds

Central Selective Acetylcholinesterase Inhibitor with Neurotrophic Activity Structure-Activity Relationships of TAK-147 and Related Compounds

N‐Benzyl piperidine Fragment in Drug Discovery

Combination of a novel antidementia drug FK960 with donepezil synergistically improves memory deficits in rats

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