New lipophilic terbutaline ester prodrugs with long effect duration

Two new lipophilic terbutaline ester prodrugs - the biscarbamate bambuterol (pINN) and the cascade ester D 2438 - have been designed with the goal to achieve enhanced absorption and high hydrolytic stability during first-pass in order to prolong the effect duration of the parent compound. Bambuterol, the bis-N,N-dimethyl-carbamate of terbutaline, displays improved hydrolytic stability, partly by inhibition of its own hydrolysis, and has been shown to survive first-pass hydrolysis in the dog to a high degree. Bambuterol per se is inactive; however, after oral administration to guinea-pigs, the ED50 value for protection from histamine-induced bronchospasm is similar to that of terbutaline. Moreover, the terbutaline plasma level-time profile after oral doses of bambuterol in dogs is significantly prolonged. The cascade ester of terbutaline (D 2438), derived from p-pivaloyloxybenzoic acid, was designed to undergo first-pass hydrolysis and conjugation at the p-pivaloyloxybenzoic acid moiety; i. e. distal from the active resorcinol moiety in terbutaline. The prodrug itself is active in the isolated guinea-pig trachea and displays prolonged effect duration both after inhalation in guinea-pigs and after oral administration in dogs. The cascade ester prodrug (D 2438) has a somewhat shorter effect duration than bambuterol in these species.