Prodrugs of Vitamin E. 1. Preparation and Enzymatic Hydrolysis of Aminoalkanecarboxylic Acid Esters of d‐α‐Tocopherol

Abstract

Nine aminoalkanecarboxylic acid esters ofd‐a‐tocopherol were synthesized and evaluated as potential water‐soluble prodrugs suitable for parenteral administration. The hydrochloric acid salts of the esters were soluble in water. The kinetics of hydrolysis of the esters was studied in isotonic phosphate buffer, rat plasma, human plasma, and rat liver homogenate at 37°C. The hydrolysis of the esters was proved to be catalyzed by liver esterases. The susceptibility of the esters to undergo liver esterase hydrolysis was affected by the structure of the amino functionality and size of the acyl moiety on the promoiety. TheN‐methylaminoacetyl andN, N‐dimethylaminoacetyl esters ofd‐α‐tocopherol were more rapidly hydrolyzed thand‐α‐tocopheryl acetate, a commercially availabled‐α‐tocopheryl ester. These results suggested that the salts of theN,N‐dimethylaminoacetyl esters are promising prodrug candidates ofd‐α‐tocopheryl for parenteral use.