A prodrug approach to increasing the oral potency of a phenolic drug. 1. Synthesis, characterization, and stability of an O-(imidomethyl) derivative of 17β-estradiol

An O‐(saccharinylmethyl) prodrug was synthesized to improve the poor oral potency of the phenolic drug 17β‐estradiol. This O‐(imidomethyl) type of prodrug was designed to undergo chemical hydrolysis and to be a poor substrate for enzymatic hydrolysis. At 37 °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 sodium fluoride into rat plasma had no significant effect on the half‐life. Thus, the observed increased rate of hydrolysis in biological media is not due to enzymatic catalysis but to a nonspecific solventlike effect. The fact that the rate of hydrolysis in the methanol:buffer exhibited a first‐order dependence on the hydroxide ion concentration and that the rate of hydrolysis increased with increasing methanol concentrations up to 70% supported an S2 mechanism of hydrolysis for the prodrug. These results suggest that an O‐(imidomethyl) type prodrug is insensitive to enzymatic catalysis of hydrolysis yet may hydrolyze quickly enough to release 17β‐estradiol faster than 17β‐estradiol is conjugated and excreted. Copyrigh