To confirm recent in vitro findings, we examined the cardiovascular and electrocardiographic (ECG) effects of the dopamine receptor agonists ropinirole, apomorphine, and PNU-142774E in conscious dogs. Intravenous (i.v.) infusions of ropinirole totaling 20 microg/kg maximally reduced mean arterial pressure (MAP; -16 mm Hg) and the ECG PR interval (-13 milliseconds) and increased heart rate (HR; +29 b/min) and QTc length (+33 ms) at a peak plasma drug concentration (p[drug]) of 3.5 ng/ml. I.V. PNU-142774E was better tolerated through 66 microg/kg and a maximal p[drug] of 5.9 ng/ml with negligible cardiovascular changes and mild QTc reduction (13 ms). Apomorphine (25 microg/kg i.v.) was intermediate to ropinirole and PNU-142774E for emesis and peak changes in MAP (-6 mm Hg), HR (+24 b/min), and QTc (+15 milliseconds) at a mean p[drug] of 3.4 ng/ml. By comparison, the class III antiarrhythmic trecetilide (2.0 mg/kg bolus) increased QTc (+58 ms) without affecting mean arterial pressure or heart rate. This study establishes that in conscious dogs, the selective dopamine receptor agonist PNU-142774E has fewer cardiovascular and emetic effects than ropinirole and apomorphine and supports prior in vitro findings that ropinirole and apomorphine but not the PNU-142774E imidazoquinolin analog sumanirole reduces the delayed rectifier current in HERG transfected cells.

01 Oct 2003·Current Medicinal Chemistry-Cardiovascular & Hematological Agents

IKr Channel Blockers: Novel Antiarrhythmic Agents

Review

Author: Kim, H. Y. ; Park, J. Y. ; Kwon, L. S. ; Lee, K. ; Ryu, P. D.

There have been extensive efforts to develop I(Kr) channel blockers as a new antiarrhythmic agent for atrial or ventricular fibrillation, since it was demonstrated that selective blockade of the rapidly activating delayed rectifier K+ channel (I(Kr)) in the heart is not deleterious for the total mortality in fatal ventricular arrhythmia patients. Among them, dofetilide and KCB-328 blocks the I(Kr) specifically. Therefore, it increases the action potential duration (APD) selectively. Ibutilide, trecetilide, nifekalant, dronedarone, BRL-32872, H345/52 and ersentilide block the I(Kr). However, they modify also other cardiac channels or receptors. The frequency dependence of the compounds in prolonging the APD varies from the strong reversed tendency of dofetilide to the relatively neutral profile of KCB-328 and BRL-32872. Every compound reported so far has a proarrhythmic potential of torsade de pointes induction under certain conditions, although depending on the structure, the intensity may be somewhat different. In the coming decade, efforts to improve the reverse frequency dependence profile of the I(Kr) blockers by optimizing the onset and recovery time constant of the HERG block (e.g. KCB-328, vesnarinone) or the balance between the block of I(Kr) and Ca++ channels in the heart (e.g. BRL-32872, H 345/52) to eliminate the proarrhythmic potential of the currently known I(Kr) blockers are warranted. Further trials are also needed to discover more favorable compounds with multiple receptors including I(Kr) (e.g. nifekalant, dronedarone) for treating ventricular arrhythmias.

01 Mar 2001·Journal of Medicinal ChemistryQ1 · MEDICINE

Progress toward the Development of a Safe and Effective Agent for Treating Reentrant Cardiac Arrhythmias: Synthesis and Evaluation of Ibutilide Analogues with Enhanced Metabolic Stability and Diminished Proarrhythmic Potential

Q1 · MEDICINE

Article

Author: Imbordino, Rick J. ; Gibson, John K. ; Buchanan, Lewis V. ; Perricone, Salvatore C. ; Walters, Rodney R. ; Emmert, D. Edward ; Glavanovich, Michael A. ; Hester, Jackson B. ; Clark, Michael A. ; Squires, Donald M. ; Cimini, Madeline G. ; McMillan, Moses W. ; LeMay, Richelle J.

A series of ibutilide analogues with fluorine substituents on the heptyl side chain was prepared and evaluated for class III antiarrhythmic activity, metabolic stability, and proarrhythmic potential. It was found that fluorine substituents stabilized the side chain to metabolic oxidation. Many of the compounds also retained the ability to increase the refractoriness of cardiac tissue at both slow and fast pacing rates. The potential for producing polymorphic ventricular tachycardia in the rabbit model was dependent on the chirality of the benzylic carbon. The S-enantiomers generally had less proarrhythmic activity than the corresponding racemates. One compound from this series (45E, trecetilide fumarate) had excellent antiarrhythmic activity and metabolic stability and was devoid of proarrhythmic activity in the rabbit model. It was chosen for further development.

100 Deals associated with Trecetilide Fumarate

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Indication	Highest Phase	Country/Location	Organization	Date
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