Kinetics of rearrangement and hydrolysis of amino acid derivatives of prazosin

Amino acid amides of prazosin have been synthesized as potential prodrugs to increase the water solubility of the parent compound and target peptidase enzymes for cleavage of the prodrug in vivo (bioreversion). The α-amino acid derivatives degraded rapidly in aqueous solution at pH values > 5 with half-lives on the order of 10-50 min. The rapid degradation of these derivatives was attributed to intramolecular nucleophilic attack of the α-amine of the amino acid resulting in a rearranged product, not prazosin. In the absence of a free α-amino group, greater stabilization was achieved and the primary route of degradation at all pH values was hydrolysis of the amide bond to give prazosin.