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

The thiadiazinone derivatives EMD 60417, EMD 66430. and EMD 66398 were deve loped as class III antiarrhythmic agents. Their chemical structure is close ly related to that of their calcium-sensitizing congener [+]-EMD 60263, and EMD 66398 possesses the methylsulfonylaminobenzoyl moiety present in the p rototypical 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 p atch-clamp technique. The test compounds' class III action. which is relate d to impairment of K+ channel function, was confirmed by action potential m easurements, EMD 60417, EMD 66430. EMD 66398, and almokalant (I LM each) re versibly prolonged the action potential duration in guinea-pig myocytes. In the same cells, the rapidly activating component I-Kr of the delayed recti fier K+ current, which has been defined by its sensitivity to E-4031, was r educed by EMD 60417. EMD 66430. EMD 66398. and almokalant. Inhibition of I- Kr was concentration-dependent as determined by attenuation of tail current s. The slowly activating component IK, of the delayed rectifier K+ current was not affected. The inward rectifier K+ current I-K1 was not influenced a t potentials close to the reversal potential. Transient and sustained outwa rd K+ currents ( I-to, I-so) measured in human atrial myocytes were not alt ered by any EMD compound. L-type Ca2+ current was hardly affected at concen trations of 1-10 muM, but sodium current was decreased. Action potential pr olongation 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 IK, than EMD 60417 and EMD 66430. an d thus resembles E-4031 in structure and function.