CHEMICAL AND PLASMA HYDROLYZES OF A DIPHENYL ALPHA-AMINOMETHYL PHOSPHONATE PRODRUG INHIBITOR OF NEUTRAL ENDOPEPTIDASE-24.11

The rate and product selectivity of the hydrolysis of CGS 25462 (1), a n orally active diphenyl phosphonate prodrug of a potent neutral endop eptidase 24.11 inhibitor, has been studied in acidic and basic solutio ns and in the plasma of four species. While the chemical hydrolysis of 1 generally afforded the monophenyl phosphonate intermediate 2, furth er conversion to the bioactive phosphonic acid 3 occurred in bicarbona te solution. Concerning the generation of 3 from a in plasma, the data are consistent with the involvement of a biological catalysis, which may also apply in the hydrolysis of the prodrug in vivo.