O N H

CH3 NH2

Figure 3.10 Amprenavir (a) and fosamprenavir (b).

tenofovir, a nucleotide reverse-transcriptase inhibitor (NRTI) particularly useful for treating HIV patients with early therapeutic failure.48,49 Tenofovir undergoes phosphorylation and forms tenofovir diphosphate, which is a potent and selective inhibitor of viral reverse-transcriptor enzyme. Tenofovir is a dianion at physiological pH with a low partition coefficient, which results in low and erratic oral bioavailability. However, tenofovir disoproxil, a bis-isopropoxyl carbonate derivative, exhibits excellent chemical stability and a bioavailability of approximately 30 percent in dogs. Afumarate salt of tenofovir disoproxil is used to minimize dimerization of the tenofovir disoproxil with degradation product formaldehyde. Tenofovir disoproxil fumarate (Fig. 3.11) is nonhygro-scopic and stable and exhibits rapid dissolution and an oral bioavail-ability of 43 percent in humans. Typical salt prodrugs and their applications are summarized in Table 3.4.

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