Background:  HIV-1 reverse transcriptase is a key target for the inhibition of viral replication. However, treatment with regimens containing non-nucleoside reverse transcriptase inhibitors (NNRTI) often lead to resistance due to drug-specific mutations, leaving patients with no further NNRTI options.

Methods:  Advanced 8-substituted dipyridodiazepinone derivatives were used as a starting point for the identification of new inhibitors with a broader antiviral profile and promising pharmacokinetic parameters. Optimization was guided by reverse transcriptase inhibition and cell-based assay using a panel of clinically relevant reverse transcriptase 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 pharmacokinetic evaluation.

Results:  Following SAR on a series of inhibitors having a quinolinyloxyethyl substitutent at C-8, a new series of molecules containing a benzoic acid moiety were identified. This series of inhibitors had EC₅₀ values below 15 nM for the inhibition of recombinant HIV-1 containing both the K103N and Y181C mutations. Good antiviral activity against this double mutant was found to be predictive of a broad profile against other clinically relevant mutants. Members of this series have demonstrated excellent pharmacokinetic profile in rats, dogs and monkeys. A detailed DMPK characterization of representative inhibitors which led to the selection of an advanced candidate will be described.

Conclusions:  We have identified a novel series of inhibitors with broad-spectrum of activity against wild type as well as clinically relevant NNRTI-resistant HIV-1 mutants.

Keywords: NNRTI; ANTIRETROVIRAL THERAPY; INHIBITION