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

Multiple delayed rectifier potassium currents, including IKs, 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 IKs blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.