We report a direct β-alkylation of ketones and aldehydes with simple alkyl bromides through a Pd-catalyzed redox-cascade strategy. The use of a Cu cocatalyst is important for improved efficiency. The reaction is redox-neutral, without the need for strong acids or bases. Both cyclic and acyclic ketones, as well as α-branched aldehydes, are suitable substrates for coupling with secondary and tertiary alkyl bromides. Concise formal synthesis of Zanapezil is achieved using this β-alkylation method.

01 Aug 2005·British Journal of PharmacologyQ2 · MEDICINE

Effect of oral administration of zanapezil (TAK‐147) for 21 days on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats

Q2 · MEDICINE

Article

Author: Katsunori Iwasaki ; Izzettin Hatip-Al-Khatib ; Tomoaki Ikeda ; Yoshitaka Yoshimitsu ; Michihiro Fujiwara ; Nobuaki Egashira ; Takashi Arai ; Kenichi Mishima

Zanapezil (TAK‐147 (3‐[1benzylpiperdin‐4‐yl]‐1‐(2,3,4,5‐tetrahydro‐1 H‐1‐benzazepin‐8‐yl) propan‐1‐one fumarate)) is a selective acetylcholine (ACh) esterase inhibitor under investigation as a drug for Alzheimer's disease (AD) treatment.

In this study, the effects of TAK‐147 at 2 mg kg−1 p.o. for 21 days, compared to donepezil (E2020), on the levels of ACh, catecolamines and indoleamines were investigated in the ventral hippocampus (VH) of freely moving rats by microdialysis‐high‐performance liquid chromatography.

The results revealed that the VH contains 92.05±21.97 fmol 20 μl−1 ACh and the following monoamines levels (pg 30 μl−1), norepinephrine (NE) 1.92±0.39, epinephrine (Epi) 1.91±0.183, 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) 11.53±3.22, normetanephrine 3.26±0.61, dopamine (DA) 0.77±0.23, 3,4‐dihydroxyphenylacetic acid (DOPAC) 3.37±1.01, homovanillic acid (4‐hydroxy‐3‐methoxyphenylacetic acid; HVA) 4.04±0.93, 3‐methoxytyramine 0.64±0.13, serotonin (5‐HT) 0.73±0.16 and 5‐hydroxyindoleacetic acid (5‐HIAA) 313.15±18.42.

On the 21st day and prior to the last dose, TAK‐147 increased ACh, Epi, DA and 5‐HT, whereas E2020 increased MHPG, Epi and DA. Following the last dose, TAK‐147 increased NE, whereas E2020 increased NE, ACh and 5‐HT in addition to their effects prior to the last dose. TAK‐147 decreased HVA : DA ratio, but only marginally decreased DOPAC : DA and 5‐HIAA : 5‐HT ratios. On the other hand, E2020 decreased ratios of HVA : DA, DOPAC : DA (prior to the last dose), and 5‐HIAA : 5‐HT (90–180 min after the last dose). Both drugs decreased MHPG : NE only at 180 min after the last dose. The results also showed that TAK‐147 increased Epi : NE ratio prior to and for 120 min following the last dose, whereas E2020 increased the ratio only before the last dose. The present results show that TAK‐147 at a subthreshold dose could differentially increase ACh and 5‐HT, compared to MHPG increased by E2020. The last dose of each drug could extend their effects to other monoamines.

The increase of the monoamines levels, in addition to that on the ACh, and decrease of their oxidation could be of value in the treatment of the AD, other dementic diseases and the cohort neurological disorders depending on the type of the monoamine underlying the disorder.

British Journal of Pharmacology (2005) 145, 1035–1044. doi:10.1038/sj.bjp.0706288

01 Jun 2004·Brain ResearchQ4 · MEDICINE

Comparison of the effect of TAK-147 (zanapezil) and E-2020 (donepezil) on extracellular acetylcholine level and blood flow in the ventral hippocampus of freely moving rats

Q4 · MEDICINE

Article

Author: Michihiro Fujiwara ; Nobuaki Egashira ; Izzettin Hatip-Al-Khatib ; Katsunori Iwasaki ; Arai Takashi

The effects of zanapezil (TAK-147) and donepezil (E2020) on extracellular acetylcholine (ACh) levels were investigated by HPLC-microdialysis of ventral hippocampus (VH) in freely moving intact rats. The results showed that the basal ACh release rate in the VH is 116.7 +/- 12.4 to 158.4 +/- 22.86 fmol/20 microl. At 2, 5 and 10 mg/kg, single p.o., each drug increased ACh level by 9.4%, 106.5%, 50.8% (TAK-147) and 14.8%, 76.1%, 120.94% (E2020), respectively. The ED50 values were 4.52 mg/kg (1.43 - 14.29; R=0.52) and 4.07 mg/kg (1.77 - 9.37; R=0.985) for TAK-147 and E2020, respectively. Analysis of data revealed that the relative TAK-147/E2020 potency ratio is 0.773, but the effect of E2020 was accompanied by more prominent skeletal muscle fasciculation, gnawing, increased defecation and to lesser extent salivation. Moreover, the significant effect of TAK-147 was observed earlier (20 min) than E2020 (60 min). In this study, we also investigated the effect of both drugs at dose of 5 mg/kg p.o. on blood flow in the VH using Laser Doppler Flowmetry. The results showed that the average blood flow rate in the VH is 6.5 +/- 0.9 ml/min/100 g. TAK-147 did not change blood flow, but E2020 increased blood flow in a biphasic manner. The first increment was obtained between 5 and 40 min (11.5 +/- 2.2 to 12.7 +/- 2.2 ml/min/100 g), and the second one 80-105 min (10.7 +/- 1.6 to 13.4 +/- 3.6 ml/min/100 g). In conclusion, the present results indicate that both TAK-147 and E2020 increase ACh level in the VH. E2020 showed greater potency than TAK-147, but it induced more fasciculation and other side effects than TAK-147. Moreover, the blood flow increasing properties of E2020 could be beneficial in some patients with Alzheimer' disease especially those with chronic vascular dementia, but at the same time, it could also indicate less specific ACh increasing activity than TAK-147 and higher risk of cerebral hemorrhage. On the other hand, the fast and specific effect of TAK-147 may be useful for cure of early stages of Alzheimer's disease (AD).

100 Deals associated with Zanapezil Fumarate

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KEGG	Wiki	ATC	Drug Bank
D09835	-	-	DB04859

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 3	JP	Takeda Pharmaceutical Co., Ltd.	-

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