JNJ 303 is a potent blocker of the slow component of delayed rectifier potassium current (IKs) [1] with an IC50 value of 0.064 μM [2].

Accompanied by the transient outward current (Ito), IKs channel is a main potassium channel that affects cardiac repolarisation and thus the length of the QT interval [2].

Dofetilide accompanied by JNJ 303 resulted in an additional 80% field potential prolongation. Sotalol administration with JNJ 303 in hPSC-CM resulted in an additional maximum prolongation of field potential (FP) duration of ~25% of cells. JNJ 303 treatment in a patient-derived hiPSC line led to a maximum 30% prolongation, this prolongation is significantly more than that in the control hPSC-CM. JNJ 303 had minor effect on the repolarization of spontaneously beating human pluripotent stem cells (hPSC-CM) [1].

The addition of IKs blockade to IKr blockade gave at least additive QT prolongation and even torsades de pointes (TdP). Treatment with JNJ 303 resulted in spontaneous events of a “pause-dependent” TdP nature in an anaesthetised dog model. Treatment with JNJ 303 made at least two animals die unexpectedly in early pharmacokinetic or pharmacological studies. Compared with other tested sulphonamide analogue in an adrenergic-dependent TdP dog model, JNJ 303 bore a much reduced IKr (hERG, rapidly activating delayed inward rectifier potassium channel) blocking activity with an IC50 value of 12,640 nM and a higher potency on the 11β-hydroxysteroid dehydrogenase-1 (HSD1) [2].

References:
[1]. S. R. Braam, L. Tertoolen, S. Casini, et al. Repolarization reserve determines drug responses in human pluripotent stem cell derived cardiomyocytes. Stem Cell Research, 2013, 10:48-56.
[2]. Rob Towart, Joannes T.M. Linders, An N. Hermans, et al. Blockade of the IKs potassium channel: An overlooked cardiovascular liability in drug safety screening Journal of Pharmacological and Toxicological Methods, 2009, 60: 1-10.