Three thiadiazinone derivatives, EMD 60417, EMD 66430, and EMD 66398, with class III antiarrhythmic activity but different electrophysiologic profiles.

The thiadiazinone derivatives EMD 60417, EMD 66430, and EMD 66398 were developed as class III antiarrhythmic agents. Their chemical structure is closely related to that of their calcium-sensitizing congener |+|-EMD 60263, and EMD 66398 possesses the methylsulfonylaminobenzoyl moiety present in the prototypical I Kr blocker E-4031, We compared the electrophysiologic effects of these compounds with standard drugs (almokalant, E-4031, quinidine) in cardiac myocytes from guinea-pig ventricle and human atrium by whole-cell patch-clamp technique. The test compounds' class III action, which is related to impairment of K + channel function, was confirmed by action potential measurements. EMD 60417, EMD 66430, EMD 66398, and almokalant (1 μM each) reversibly prolonged the action potential duration in guinea-pig myocytes. In the same cells, the rapidly activating component I Kr of the delayed rectifier K + current, which has been defined by its sensitivity to E-4031, was reduced by EMD 60417, EMD 66430, EMD 66398, and almokalant. Inhibition of I Kr was concentration-dependent as determined by attenuation of tail currents. The slowly activating component I Ks of the delayed rectifier K + current was not affected. The inward rectifier K + current I K1 was not influenced at potentials close to the reversal potential. Transient and sustained outward K + currents (I to , I so ) measured in human atrial myocytes were not altered by any EMD compound. L-type Ca 2+ current was hardly affected at concentrations of 1-10 μM, but sodium current was decreased. Action potential prolongation by EMD 60417, EMD 66430, and EMD 66398 is due to block of I Kr . I Na is inhibited at higher concentrations by EMD 66430 and EMD 60417. EMD 66398 is more potent and selective for I Kr than EMD 60417 and EMD 66430, and thus resembles E-4031 in structure and function.