Molecular Design and Development of Potassium Channel Blockers

During the past decade, much attention has been directed toward the development of potassium channel blockers, which were expected to be a novel type of antiarrhythmic agent. Pharmacological screening for new cardiovascular agents led us to discover the potassium channel blocking activity of MS-3579 which we originally prepared as a β-blocking agent. Since MS-3579 lacks potency as a class III agent and its (aryloxy) propanolamine moiety was thought to be the typical β-blocking pharmacophore, we decided to manipulate this moiety to diminish β-blocking activity and potentiate class III activity. In this paper we introduce the development of Nifekalant Hydrochloride, which selectively modulates potassium channel and homogeneously prolongs the transmembrane action potential duration (APD) and consequently, refractoriness, without slowing intercardiac condition, and can terminate reentry. Nifekalant Hydrochloride was approved and launched as the first class III antiarrhythmic agent, developed in Japan.