Design and Synthesis of Novel Isoquinoline-3-nitriles as Orally Bioavailable Kv1.5 Antagonists for the Treatment of Atrial Fibrillation

Novel 3-cyanoisoquinoline Kv1.5 antagonists have been prepared and evaluated in in vitro and in vivo assays for inhibition of the Kv1.5 potassium channel and its associated cardiac potassium current, IKur. Structural modifications of isoquinolinone lead 1 afforded compounds with excellent potency, selectivity, and oral bioavailability.