Cardiovascular Assessment of ER-118585, a Selective Phosphodiesterase 5 Inhibitor (Pharmacology)

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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 monohydrochloridc. The present results indicated that 1) ER-118585 significantly inhibited the human ether-a-go-go related gene (HERG) tail current at 10nM and above with an IC_<50> value of 40.7nM in human embryonic kidney 293 cells transfected with HERG cDNA; 2) ER-118585 at 100 and 1000 niw 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 10μg/kg/min significantly prolonged the QT interval by 10.5±1.6% from 281 ±2 ms to 311±6ms in six anesthetized dogs subjected to atrial pacing. In consideration of both the plasma concentration of ER-118585 (984±78nM, n=3) and its protein binding fraction (99.0±0.1%, n=5), the free plasma concentration was estimated at 9.8±0.8nM, 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.
公益社団法人日本薬学会の論文
2003-12-01