New bis(SATE) prodrug of AZT 5 '-monophosphate: In vitro anti-HIV activity, stability, and potential oral absorption

The in vitro anti-HIV activity, stability, and potential for oral absorptio n of a phosphotriester derivative of AZT (zidovudine; 3'-azido-2',3'-deoxyt hymidine) bearing a new esterase-labile S-acyl-2-thioethyl (SATE) group as transient phosphate protection are reported. The biolabile protection is ch aracterized by the presence of a hydroxyl function in the acyl chain. In ac cordance with previously reported data in the bis(SATE) prodrug series, the present results demonstrate that the studied bis(hydroxy tBuSATE)phosphotr iester exerts its biological effects via intracellular delivery of the 5'-m onophosphate of AZT. The hydroxyl function confers a high resistance agains t; esterase hydrolysis, and the studied prodrug is able to cross the Caco-2 cell monolayers in intact form, suggesting that its further development as a possible anti-HIV pronucleotide candidate is warranted, (C) 2001 Wiley-L iss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:448-46 3, 2001.