Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors

Integrase mutations can reduce the
effectiveness of the first-generation
FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir
(RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir
(DTG), has enjoyed considerable clinical success; however, resistance-causing
mutations that diminish the efficacy of DTG have appeared. Our current
findings support and extend the substrate envelope concept that broadly
effective INSTIs can be designed by filling the envelope defined by
the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides
as an INSTI scaffold, making a limited set of derivatives, and concluded
that broadly effective INSTIs can be developed using this scaffold.
Herein, we report an extended investigation of 6-substituents as well
the first examples of 7-substituted analogues of this scaffold. While
7-substituents are not well-tolerated, we have identified novel substituents
at the 6-position that are highly effective, with the best compound
(6p) retaining better efficacy against a broad panel
of known INSTI resistant mutants than any analogues we have previously
described.