Selective class III antiarrhythmic agents. 1. Bis(arylalkyl)amines

Abstract

A series of bis(arylalkyl)amines is described and their effects on prolonging effective refractory period in isolated cardiac tissue listed. Most compounds prolonged the cardiac action potential without significantly altering the maximum rate of depolarization and may be defined as selective class III antiarrhythmic agents. It was found that a particularly advantageous structural feature was to have a methanesulfonamido moiety on both of the aryl rings. Thus, compound 16 [1-(4-methanesulfonamidophenoxy)2-[N-(4-methanesulfonamidophene thyl)-N- methylamine]ethane] was selected for further investigations. The compound is highly potent and selective class III agent which acts by blockade of cardiac potassium channels.

Exploring Chemical Substructures Essential for hERG K+ Channel Blockade by Synthesis and Biological Evaluation of Dofetilide Analogues

“…The unsubstituted analogue 19 displayed an affinity of 48 nm (calculated pK a~8 .99). N-Alkylation with CH 3 (35) and CH 2 CH 3 (54) substituents increased the pK a of the basic nitrogen (35, pK a~9 .27; 54, pK a~9 .61) leading to an increased hERG affinity (35, K i = 6 nm; 54, K i = 1.2 nm). Abolishing the basicity of the nitrogen by acylation (55, pK a~1 .80; 56 pK a = À4.95) resulted in decreased hERG affinity (K i = 278 and 162 nm, respectively).…”

“…In this study we take a different approach by assuming that design and synthesis of compounds primarily for the hERG channel as the main target can afford more precise structure-activity relationships (SAR) and can facilitate the discovery of chemical alerts for hERG potassium channel toxicity. Dofetilide (1) [35] was selected as the lead scaffold from which hERG channel inhibitors can be developed. It is a member of a methanesulphonanilide class of antiarrhythmic drugs with high affinity for the hERG channel.…”

Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle

“…Dofetilide (UK-68,798) is a newly developed methanesulfonamide derivative, 1-(4-methanesulfonamidophenoxy)-2-[N-(4-methanesulfonamidophenethyl)-Nmethylamino]ethane [1]. In nanomolar concentrations this compound has been demonstrated to effectively increase action-potential duration (APD) and effective refractory period (ERP) in cardiac tissues from guinea pig [2] and dog [3,4] without affecting cardiac conduction [3].…”

UK‐68,798, A Class III Antiarrhythmic Drug with Antifibrillatory Properties

“…1992 elimination half-life of UK-68,798 was 4-6 h (0.254). 167 h-'), the volume of distribution was 4.0 L, and the clearance rate was 1.2 ml/min/kg (7). The oral bioavailability of UK-68,98 in the dog was determined to be between 72 and 100% (7).…”