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New Antiretroviral Agents: RTI's and PI's
Wednesday, 1:30 - 3:30 pm
Background: Non-nucleoside reverse transcriptase inhibitors (NNRTI) are potent components of combination antiretroviral therapies. However patients failing on an NNRTI-containing regimen most often exhibit broad cross-resistance to all members of the class leaving them with no further NNRTI options. A pre-requisite for a next generation of NNRTI is potent antiviral activity against clinically prevalent NNRTI-resistant variants.
Methods: Advanced derivatives of the NNRTI nevirapine (NVP) were used as starting point for the development of new chemical entities with broader antiviral profile. Optimization was guided by RT inhibition and cell-based viral replication assays using a panel of clinically relevant RT mutants (K103N, Y181C, G190A, etc). Key biopharmaceutical parameters (serum shift, metabolic stability, CYP450 inhibition) were also measured to assist in the selection of candidates for animal PK studies.
Results: Following extensive SAR, a series of nevirapine-like molecules with a quinoline extension at the C-8 position was identified. This series displays EC50 values < 1nM against wild-type virus and < 10nM against prevalent single and double mutants, along with favorable biopharmaceutical properties and pharmacokinetics. A detailed characterization of representative members of this series is provided.
Conclusions: These compounds are valuable candidates for further development.
Keywords: NNRTI; Resistance; Nevirapine