Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine

J E Starrett Jr; D R Tortolani; M J Hitchcock; J C Martin; M M Mansuri

doi:10.1016/0166-3542(92)90084-i

Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine

Antiviral Res. 1992 Sep;19(3):267-73. doi: 10.1016/0166-3542(92)90084-i.

Authors

J E Starrett Jr¹, D R Tortolani, M J Hitchcock, J C Martin, M M Mansuri

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492.

PMID: 1332606
DOI: 10.1016/0166-3542(92)90084-i

Abstract

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.

MeSH terms

Adenine / analogs & derivatives*
Adenine / chemical synthesis
Adenine / pharmacology
Antiviral Agents / chemical synthesis*
Antiviral Agents / pharmacology*
Cell Line
Cytomegalovirus / drug effects
Drug Evaluation, Preclinical
HIV / drug effects
Humans
Organophosphonates*
Prodrugs / chemical synthesis*
Prodrugs / pharmacology*
Simplexvirus / drug effects

Substances

Antiviral Agents
Organophosphonates
Prodrugs
adefovir
Adenine