A PRODRUG APPROACH TO INCREASING THE ORAL POTENCY OF A PHENOLIC DRUG .1. SYNTHESIS, CHARACTERIZATION, AND STABILITY OF AN O-(IMIDOMETHYL) DERIVATIVE OF 17-BETA-ESTRADIOL

An O-(saccharinylmethyl) prodrug was synthesized to improve the poor o ral potency of the phenolic drug 17 beta-estradiol. This O-(imidomethy l) type of prodrug was designed to undergo chemical hydrolysis and to be a poor substrate for enzymatic hydrolysis. At 37 degrees C, it was found to exhibit half-lives of about 13 min in 50% methanol:pH 7.0 (v/ v) phosphate buffer, about 3 min in rat plasma, about 15 min in human plasma, and about 50 min in 20% rat liver homogenate. Introduction of the enzyme poison tetraethyl pyrophosphate or the protein denaturant s odium fluoride into rat plasma had no significant effect on the half-l ife. Thus, the observed increased rate of hydrolysis in biological med ia is not due to enzymatic catalysis but to a nonspecific solventlike effect. The fact that the rate of hydrolysis in the methanol:buffer ex hibited a first-order dependence on the hydroxide ion concentration an d that the rate of hydrolysis increased with increasing methanol conce ntrations up to 70% supported an S(N)2 mechanism of hydrolysis for the prodrug. These results suggest that an O-(imidomethyl) type prodrug i s insensitive to enzymatic catalysis of hydrolysis yet may hydrolyze q uickly enough to release 17 beta-estradiol faster than 17 beta-estradi ol is conjugated and excreted.