Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine.
9-(2-Phosphonylmethoxyethyl)adenine (PMEA; 1) was acylated with chloromethyl pivalate to afford bis(pivaloyloxymethyl) PMEA (2). The ester prodrug demonstrated enhanced in vitro potency against HSV-2 greater than 150-fold higher than the parent compound. The antiviral activity of 2 was 50-fold better than PMEA against HSV-1, and equipotent against HIV and HCMV. The toxicity of 2 was studied in both resting and growing cells.
Starrett
J E
JE
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492.
Tortolani
D R
DR
Hitchcock
M J
MJ
Martin
J C
JC
Mansuri
M M
MM
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006678:HIV / Q000187:drug effects; D006801:Humans; D063065:Organophosphonates; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D018139:Simplexvirus / Q000187:drug effects
D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; C053001:adefovir; D000225:Adenine