作者: Fukuda, Ayumu ; Nishiya, Yoichi ; Sasho, Setsuya ; Kamigaki, Masayo ; Shibata, Kenji ; Yokokawa, Sachiko ; Yoshida, Tetsuo ; Seishi, Takashi ; Yamagata, Tsuyoshi ; Shimizu, Yukiko ; Sakuma, Takashi ; Sekine, Susumu ; Sato, Hidetaka

KW-7158 is a novel therapeutic candidate for treating overactive bladder (OAB) with a unique mode of action: suppression of sensory afferent nerves. However, the molecular target of this compound remains unknown. We herein report the identification of the KW-7158 target to be equilibrative nucleoside transporter-1 (ENT1). A membrane protein expression library of ca. 7000 genes was expressed in a dorsal root ganglion cell line, which we had previously generated, and subjected to screening for binding with a fluorescent derivative that retains high binding activity to the target. The screening revealed that only cells transfected with an ENT1 expression vector exhibited significant binding. We next performed [(3)H]KW-7158 binding experiments and an adenosine influx assay and found that KW-7158 binds to and inhibits ENT1. To further demonstrate the pharmacological relevance, we evaluated other known ENT1 inhibitors (nitrobenzylthioinosine, dipyridamole, draflazine) in an in vitro bladder strip contraction assay and the rat spinal cord injury OAB model. We found that all of the inhibitors exhibited anti-OAB activities, of which the potencies were comparable to that of adenosine influx inhibition in vitro. These studies demonstrated that the pharmacological target of KW-7158 is ENT1, at least in the rat OAB model. Our results will aid understanding of the precise mechanism of action of this drug and may also shed new light on the use of the adenosine pathway for the treatment of OAB.

2012-07-01·Xenobiotica4区 · 医学

4区 · 医学

Article

作者: Junko Ushiki ; Kazuhiro Fujita ; Takeo Nakanishi ; Hiroshi Kodaira ; Ikumi Tamai ; Hiroyuki Kobayashi ; Hiroshi Maeda

Species differences in the pharmacokinetics of KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] were studied in in vivo and in vitro experiments. The exposure ratio of hydrolyzed metabolite (M2, primary metabolite in human plasma)/KW-7158 was higher than the ratio of thiophen-to-furan converted metabolite (M1)/KW-7158 in human subjects after oral administration, but the mouse, rat and dog studies gave opposite results. M2 was produced in the highest amount by the 9000g supernatant of small intestine, followed by that of liver and kidney in human subjects. After correction for protein contents, the results obtained suggested that the small intestine plays a major role in the metabolism to M2 for the first pass effect after oral administration of KW-7158. The formation of M2 was independent of the presence of NADPH and was inhibited by various esterase inhibitors. These observations suggested that the predominant enzymes or isozymes involved in the formation of M2 are esterases, which differ between humans and animals. Such differences may be one of the reasons for the species differences in the pharmacokinetics of KW-7158 between humans and animals.

2012-05-01·Arzneimittelforschung

Novel LC-MS/MS Method for Simultaneous Quantification of KW-7158, a New Drug Candidate for Urinary Incontinence and Bladder Hyperactivity, and its Metabolites in Rat Plasma: A Pharmacokinetic Study in Male and Female Rats

Article

作者: Nakanishi, T. ; Kobayashi, H. ; Maeda, H. ; Tamai, I. ; Ushiki, J. ; Fujita, K.

To investigate the pharmacokinetics of KW-7158 (CAS 214763-95-8), a new drug candidate for urinary incontinence and bladder hyperactivity, in male and female rats, we developed and validated a simultaneous quantification method for KW-7158 and its 2 metabolites, M1 and M2, in plasma using high performance liquid chromatography-tandem mass spectrometry with positive/negative ion-switching scan mode. The method was selective and sensitive to KW-7158, M1 and M2 with overall precision expressed as coefficient of variance less than 11.8% and accuracy (relative error) within ± 13.7% in intra- and inter-assay variability. This method was used to determine the plasma concentration of KW-7158, M1 and M2 after intravenous and oral administration of KW-7158 in male and female rats. KW-7158 was detected as a primary constituent in plasma in both administration routes. M1 was a major metabolite with the concentration ratio of 10-20% of KW-7158, and M2 was a minor metabolite. Pharmacokinetics of KW-7158 after oral administration was considered to be linear at doses from 0.01 to 1 mg/kg. Bioavailability was relatively high with the values of 69.4 ± 17.1% and 82.6 ± 20.0% at a dose of 0.1 mg/kg in male and female rats, respectively. There was a little gender difference in pharmacokinetics of KW-7158 and its metabolites in rats.

100 项与 KW-7158 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05498

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
肠易激综合征	临床2期	日本	Kyowa Kirin Co., Ltd.	-
膀胱过度活动症	临床2期	美国	Kyowa Hakko Bio Co., Ltd.	-
膀胱过度活动症	临床2期	欧盟	Kyowa Hakko Bio Co., Ltd.	-
膀胱过度活动症	临床2期	欧盟	Kyowa Kirin Co., Ltd.	-
膀胱过度活动症	临床2期	美国	Kyowa Kirin Co., Ltd.	-
膀胱过度活动症	临床2期	日本	Kyowa Kirin Co., Ltd.	-
膀胱过度活动症	临床2期	日本	Kyowa Hakko Bio Co., Ltd.	-
急迫性尿失禁	临床2期	-	Kyowa Kirin Co., Ltd.	-