Highly stable and water soluble amino acid phosphomonoester amidates of acyclovir (ACV) were synthesized and shown to function predominantly as prodrugs of ACV and not acyclovir monophosphate (ACV-MP) with activities within two fold of the amino acid prodrug of ACV, valaciclovir (VACV). Metabolism studies revealed that incubation of cell-free extracts of Vero cells with the L-leucine phosphomonoester amidate of ACV (3c), resulted in a burst of ACV-MP production followed by the rapid generation of ACV.
Bibliographical noteFunding Information:
This work was partially supported by grant CA61909 (C.R.W.) from the National Institute of Health, the University of Minnesota Graduate School (C.R.W.), the Georgia Veterans Affairs Research Center for AIDS and HIV Infections (R.F.S.) and AI-(R.F.S.). E.J.M. was supported by the National Institutes of Health Pharmacological Training Grant, GM07994. We thank Dr. Robert Vince for his gift of a sample of (-)- carbovir and Dr. W. Thomas Shier for a gift of Vero cells.