Design and Synthesis of 4-Substituted Benzamides as Potent, Selective, and Orally Bioavailable <i>I</i><sub>Ks</sub> Blockers

Multiple delayed rectifier potassium currents, including <i>I</i><sub>Ks</sub>, are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound <b>5</b> produced <b>19(S)</b> that is the most potent <i>I</i><sub>Ks</sub> blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced <b>24A</b> with 23% oral bioavailability.