The HIV-1 integrase enzyme, one of three virus-encoded enzymes, plays an important role in retroviral replication. After reverse transcription into a double stranded DNA, the integrase, as part of a pre-integration complex, migrates into the nucleus and proceeds to insert the viral genome into the host chromosome via a multi-step process. The two enzymatic steps in this insertion process are cleavage and strand transfer. Although interrupting either of these steps could, in principle, lead to inhibition of viral replication, compounds that inhibit the strand transfer reaction were found to exhibit antiviral activity, leading to FDA approval of the strand transfer inhibitor, Isentress�. A systematic SAR survey of C2-substitutents led to the identification of furan and pyran derivatives as optimal moieties for combining antiviral potency and good animal pharmacokinetic profiles. In this study, we disclose the synthesis, antiviral activity and pharmacokinetic properties of C2-C-linked heterocyclic-5-hydroxy-6-oxo-dihydropyrimidine-4-carboxamides as novel strand transfer inhibitors.

Synthesis and HIV-1 integrase inhibitory activity of C2-C-linked heterocyclic-5-hydroxy-6-oxo-dihydropyrimidine-4-carboxamides

240th National Meeting (2010)

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