Prodrugs for improved oral beta-estradiol bioavailability.

Prodrugs of beta-estradiol (1) were prepared with the objective of improving its oral bioavailability. beta-Estradiol-3-acetylsalicylate (2), beta-estradiol-3-salicylate (3), and beta-estradiol-3-anthranilate (4) were synthesized. With these prodrugs the 3-phenolic hydroxy group of estradiol was protected, so that first-pass conjugative metabolism could be reduced. Prodrug hydrolysis rates in dog and human plasma in vitro were determined. Deacetylation of estradiol-3-acetylsalicylate was much more rapid than its hydrolysis to estradiol. In dogs, oral estradiol bioavailability after administration of 2 and 4 was 17-fold and 5-fold higher, respectively, than after oral 1.