Soft Drugs VI. The Application of the Inactive Metabolite Approach for Design of Soft β-Blockers1?2

The “inactive metabolite approach” was used to design β-blockers. The acidic inactive metabolite of metoprolol [4-(2-hydroxy-3-isopropylamino) propoxyphenylacetic acid] was used as the lead compound. Its esters (alkyl and cycloalkyl) were found active in vivo while reverting quantitatively to the same inactive metabolite in plasma. The cyclohexyl ester showed the best activity, which was cardioselective, similar to the parent compound metoprolol. Although most esters had a plasma half-life of approximately 1 min, their activity (antagonism of isoproterenol induced increase in heart rate) following intravenous administration lasted 45–90 minutes, and the maximum β-blockade was observed at 45–60 minutes in both rats and dogs.