title: Cardiovascular assessment of ER-118585, a selective phosphodiesterase 5 inhibitor.
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 IC(50) 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 microg/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.
authors.affiliation: Tsukuba Research, Drug Safety Research Laboratories, Eisai Co., Ltd. Tesukuba, Ibaraki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuno
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Adachi
authors.forename: Junko
authors.initials: J
authors.lastname: Kimura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sawa
authors.forename: Motoharu
authors.initials: M
authors.lastname: Kakiki
authors.forename: Kate
authors.initials: K
authors.lastname: Lansdell
authors.forename: Mamoru
authors.initials: M
authors.lastname: Saito
authors.forename: William David
authors.initials: WD
authors.lastname: Kerns
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002304:Cardiac Pacing, Artificial; D002318:Cardiovascular Diseases / Q000188:drug therapy; D002460:Cell Line; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D004594:Electrophysiology; D006168:Guinea Pigs; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000166:cytology; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*; D014162:Transfection / Q000379:methods; D016276:Ventricular Function / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018879:Ventricular Premature Complexes / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control
chemical_list: C494540:4-((3-chloro-4-methoxybenzyl)amino)-1-(2-hydroxy-7-azaspiro(3.5)non-7-yl)-6-phthalazinecarbonitrile monohydrochloride; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D013141:Spiro Compounds; C063968:E 4031; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human