Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
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Cardiovascular Assessment of ER-118585, a Selective Phosphodiesterase 5 Inhibitor
Hiroshi MizunoHideyuki AdachiJunko KimuraYoshio SawaMotoharu KakikiKate LansdellMamoru SaitoWilliam David Kerns
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2003 Volume 26 Issue 12 Pages 1661-1667

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Abstract

The aim of this study was to assess the cardiovascular effects of a selective phosphodiesterase 5 inhibitor ER-118585, 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinecarbonitrile monohydrochloride. The present results indicated that 1) ER-118585 significantly inhibited the human ether-a-go-go related gene (HERG) tail current at 10 nM and above with an IC50 value of 40.7 nM in human embryonic kidney 293 cells transfected with HERG cDNA; 2) ER-118585 at 100 and 1000 nM significantly increased the action potential duration (APD) at 50% and 90% repolarization in isolated papillary muscles of guinea pig; and 3) intravenous infusion of ER-118585 at 10 μg/kg/min significantly prolonged the QT interval by 10.5±1.6% from 281±2 ms to 311±6 ms in six anesthetized dogs subjected to atrial pacing. In consideration of both the plasma concentration of ER-118585 (984±78 nM, n=3) and its protein binding fraction (99.0±0.1%, n=5), the free plasma concentration was estimated at 9.8±0.8 nM, which is consistent with the minimum concentration of HERG current inhibition. In conclusion, these evaluation methods demonstrated that ER-118585 could prolong the QT interval via APD prolongation, attributable to the inhibition of the HERG potassium current.

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© 2003 The Pharmaceutical Society of Japan
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