Design and Synthesis of 4-Substituted Benzamides as Potent, Selective, and Orally Bioavailable I Ks Blockers

Multiple delayed rectifier potassium currents, including I Ks, 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 5 produced 19(S) that is the most potent I Ks blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.