Inhibitors of HIV-1 attachment. Part 9: an assessment of oral prodrug approaches to improve the plasma exposure of a tetrazole-containing derivative.

N-Acetoxymethyl 4, N-pivaloyloxymethyl 5, and N-methyl 6 were evaluated as potential oral prodrugs of the parent tetrazole 3 in rats. Prodrug 5 was ineffective in improving the plasma concentration of 3 in vivo but compound 4 provided a 15-fold enhancement of the plasma concentration of 3. Most interestingly, oral dosing of analog 6 afforded a substantial increase in the plasma concentration of 3 in rats when compared to dosing of 3. This represents a novel example of a methyl tetrazole that acts as a prodrug for a free NH tetrazole-containing compound.