Metabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates

Bis(pivaloyloxymethyl) [bis(pom)] derivatives of various acyclic nucleoside phosphonates--9-(2-phosphonylmethoxyethyl)adenine (PMEA), 9-(2-phosphonylmethoxypropyl)adenine (PMPA), and 9-(2-phosphonylmethoxypropyl)diaminopurine (PMPDAP)--were found to exhibit 9- to 23-fold greater antiviral activity than their corresponding unmodified compounds. The cytotoxicity of the bis(pom) analogs was also increased by various degrees, thus altering the therapeutic indexes of these compounds. Metabolic studies using [3H]bis(pom)PMEA and [3H]PMEA as model compounds suggested a > 100-fold increase in the cellular uptake of the bis(pom) derivative and formation of active diphosphorylated metabolite. However, the bis(pom) derivatives were chemically unstable and highly susceptible to serum-mediated hydrolysis, factors which limit their potential utility for intracellular drug delivery.