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A series of lactam sulfonamides has been discovered and optimized as inhibitors of the Kv1.5 potassium ion channel for treatment of atrial fibrillation. In vitro structure-activity relationships from lead structure C to optimized structure 3y are described. Compound 3y was evaluated in a rabbit PD-model and was found to selectively prolong the atrial(More)
OBJECTIVE To examine the electrophysiological, hemodynamic, and antiarrhythmic effects of the novel antiarrhythmic agent AZ13395438. METHODS The ion channel-blocking potency of AZ13395438 was assessed in Chinese hamster ovary cells stably expressing various human cardiac ion channels and in human atrial myocytes. The in vivo electrophysiological,(More)
The T-type calcium channel inhibitor Mibefradil was reported to protect the heart from atrial remodeling, a key process involved in the development of atrial fibrillation and arrhythmias. Mibefradil is not a selective T-type calcium channel inhibitor and also affects the function of different ion channels. Our aim was to develop a selective T-type calcium(More)
Model-based analysis of routinely generated pharmacokinetic and pharmacodynamic (PK-PD) data is a key component of preclinical drug discovery. The work process of such analyses can be automated by properly designed computer programs that reduce the number of manual steps, resulting in time saving and significantly fewer errors. Critical decisions can still(More)
A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could(More)
Chemical evolution of a HTS-based fragment hit resulted in the identification of N-(1-adamantyl)-2-[4-(2-tetrahydropyran-4-ylethyl)piperazin-1-yl]acetamide, a novel, selective T-type calcium channel (Ca(v)3.2) inhibitor with in vivo antihypertensive effect in rats.
Diphenylphosphinic amides and diphenylphosphine oxides have been synthesized and tested as inhibitors of the Kv1.5 potassium ion channel as a possible treatment for atrial fibrillation. In vitro structure-activity relationships are discussed and several compounds with Kv1.5 IC(50) values of <0.5 μM were discovered. Selectivity over the ventricular IKs(More)
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