The voltage-gated potassium channel Kv1.5 is regarded as a promising target for the development of new atrial selective drugs with fewer side effects. In the present study the discovery of ortho,ortho-disubstituted bisaryl compounds as blockers of the Kv1.5 channel is presented. Several compounds of this new class were synthesized and screened for their ability to block Kv1.5 channels expressed in Xenopus oocytes. The observed structure-activity relationship (SAR) is described by a pharmacophore model that consists of three hydrophobic centers in a triangular arrangement. The hydrophobic centers are matched by a phenyl or pyridyl ring of the bisaryl core and both ends of the side chains. The most potent compounds (e.g., 17c and 17o) inhibited the Kv1.5 channel with sub-micromolar half-blocking concentrations and displayed 3-fold selectivity over Kv1.3 and no significant effect on the HERG channel and sodium currents. In addition, compounds 17c and 17m have already shown antiarrhythmic effects in a pig model.