Prodrugs of propranolol: hydrolysis and intramolecular aminolysis of various propranolol esters and an oxazolidin-2-one derivative

Abstract

As part of a series of studies to develop prodrug derivatives of β-blockers, the O-acetyl, propionyl, butyryl and pivaloyl esters of propranolol as well as its 2-oxazolidone derivative were synthesized and their kinetics of conversion studied in aqueous solution and in 80% human plasma. The propranolol esters were all hydrolyzed to yield propranolol in solutions of pH < 7 whereas in neutral and alkaline solutions they underwent simultaneous hydrolysis and intramolecular aminolysis to produce N-acylated propranolol. The relative importance of the hydrolysis and aminolysis reactions was shown to depend on pH and on the steric properties of the acyl moiety of the esters. At pH 7.4 and 37 ° C, the half-lives of degradation of the esters to yield largely (> 90%) propranolol ranged from 85 min for the O-acetyl ester to 780 min for the O-pivaloyl ester. Human plasma catalyzed the degradation of the esters except for the O-pivaloyl ester in which case a rate-retarding effect by plasma was observed. In contrast to the esters, the oxazolidin-2-one derivative of propranolol was highly stable in aqueous solution as well as in the presence of human plasma, thus rendering it unsuitable as a prodrug form.