A Phase II, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Dose-Ranging Study Assessing the Efficacy and Safety of AC-3933 Tablets Twice Daily in Adults With Mild to Moderate Alzheimer's Disease

The purpose of this study is to investigate efficacy and safety of different doses of AC-3933 in patients with mild to moderate Alzheimer's Disease.

开始日期2006-02-01

申办/合作机构

Sumitomo Pharma America, Inc.

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项与 Radequinil 相关的文献（医药）

2016-05-01·Pharmacology Biochemistry and Behavior4区 · 心理学

AC-3933, a benzodiazepine partial inverse agonist, improves memory performance in MK-801-induced amnesia mouse model

4区 · 心理学

Article

作者: Iwamura, Yoshihiro ; Hashimoto, Takashi

AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N-methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK-801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor.

2014-12-01·European Journal of Pharmacology3区 · 医学

Procognitive effect of AC-3933 in aged mice, and synergistic effect of combination with donepezil in scopolamine-treated mice

3区 · 医学

Article

作者: Hatayama, Yuki ; Yoshida, Naoyuki ; Nakamichi, Keiko ; Hashimoto, Takashi

We have previously reported that AC-3933, a newly developed benzodiazepine receptor partial inverse agonist, facilitates acetylcholine release in the hippocampus and ameliorates scopolamine-induced memory deficits in rats. To further confirm the procognitive effect of AC-3933, we assessed in this study the beneficial effects of this compound in aged mice using the Y-maze and object recognition tests. In addition, we investigated the synergistic effect of AC-3933 and donepezil, a cholinesterase inhibitor, on scopolamine-induced memory impairment in mice. In aged mice, oral administration of AC-3933 at doses of 0.05-0.1 mg/kg and 0.05 mg/kg significantly improved spatial working memory and episodic memory, respectively. In scopolamine-treated mice, both AC-3933 and donepezil significantly ameliorated memory deficits in the Y-maze test at doses of 0.3-3 mg/kg and 10-15 mg/kg, respectively. The beneficial effect of AC-3933, but not that of donepezil, on scopolamine-induced memory impairment was antagonized by flumazenil, a benzodiazepine receptor antagonist, indicating that the procognitive action of AC-3933 arises via a mechanism different from that of donepezil. Co-administration of donepezil at the suboptimal dose of 3 mg/kg with AC-3933 at doses of 0.1-1 mg/kg significantly ameliorated scopolamine-induced memory impairment, suggesting that AC-3933 potentiates the effect of donepezil on memory impairment induced by cholinergic hypofunction. These findings indicate that AC-3933 not only has good potential as a cognitive enhancer by itself, but also is useful as a concomitant drug for the treatment of Alzheimer׳s disease.

2014-04-01·Neuroscience3区 · 医学

In vivo pharmacological characterization of AC-3933, a benzodiazepine receptor partial inverse agonist for the treatment of Alzheimer’s disease

3区 · 医学

Article

作者: Kinoshita, T ; Yoshida, N ; Kiyoshi, T ; Kohayakawa, H ; Hashimoto, T ; Nakamichi, K ; Hatayama, Y

GABAergic neurons are known to inhibit neural transduction and therefore negatively affect excitatory neural circuits in the brain. We have previously reported that 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1,6-naphthyridin-2(1H)-one (AC-3933), a partial inverse agonist for the benzodiazepine receptor (BzR), reverses GABAergic inhibitory effect on cholinergic neurons, and thus enhances acetylcholine release from these neurons in rat hippocampal slices. In this study, we evaluated AC-3933 potential for the treatment of Alzheimer's disease, a disorder characterized by progressive decline mainly in cholinergic function. Oral administration of AC-3933 (0.01-0.03mg/kg) resulted in the amelioration of scopolamine-induced amnesia, as well as a shift in electroencephalogram (EEG) relative power characteristic of pro-cognitive cholinergic activators, such as donepezil. In addition, treatment with AC-3933 even at the high dose of 100mg/kg p.o. produced no seizure or anxiety, two major adverse effects of BzR inverse agonists developed in the past. These findings indicate that AC-3933 with its low risk for side effects may be useful in the treatment of Alzheimer's disease.

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外链

KEGG	Wiki	ATC	Drug Bank
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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床2期	-	Sumitomo Pharma Co., Ltd.	-
痴呆	临床2期	美国	Hoechst Pakistan Ltd.	-
痴呆	临床2期	日本	Sumitomo Pharma Co., Ltd.	-
痴呆	临床2期	欧洲	Hoechst Pakistan Ltd.	-
阿尔茨海默症	临床1期	-	Sanofi	-
阿尔茨海默症	临床前	-	Sumitomo Pharma Co., Ltd.	-
阿尔茨海默症	临床前	-	Sanofi	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00359944 (CTgov)	临床2期	阿尔茨海默症	171	sugar pill	淵遞膚衊壓繭鹽鬱餘窪(夢憲淵構製鹽廠醖築襯) = 餘構願鹹遞壓願襯繭壓齋衊窪齋鏇鏇膚襯簾繭 (獵衊鏇網獵鑰獵築遞糧, 醖簾憲選網顧醖顧蓋衊 ~ 醖膚鏇繭衊糧夢鹹齋廠) 更多	-	2013-07-02