Integrase (IN) inhibitors are the newest class of antiretroviral agents developed for the treatment of HIV-1 infection. Merck's Raltegravir (RAL) (October 2007) and Gilead's Elvitegravir (EVG) (August 2012), which act as IN strand transfer inhibitors (INSTIs), were the first anti-IN drugs to be approved by the FDA. However, the virus develops resistance to both RAL and EVG and there is extensive cross-resistance to these two drugs. New �2nd-generation� INSTIs are needed to improve efficacy against RAL and EVG-resistant strains of IN. The FDA has recently approved the first 2nd generation INSTI, GSK's Dolutegravir (DTG) (August 2013). We report the design and synthesis series of 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides, as well as the determination of their IN inhibitory potencies in biochemical assays and their antiviral efficacies (EC50 values) in cell-based assays employing viral constructs harboring wild-type (WT) and RAL-resistant IN. Further development led to 4-amino-1-hydroxy-2-oxo-1,8-naphthyridine 3-carboxamidesthat have improved antiviral efficacies against recombinant IN in biochemical assays. These new compounds show single-digit nanomolar antiviral potencies against HIV vectors that carry wild-type (WT) IN, and have improved potency against vectors harboring the major forms of resistant mutant IN. These compounds also have low cytotoxicity in cultured cells and reach selectivity indices (CC50/EC50) over 20,000. The compounds have the potential to yield new anti-HIV drugs that are broadly effective against the known resistant mutants.

Bicyclic 4-amino-1-hydroxy-2-oxo-1,8-naphthyridine-containing compounds having high potency against Raltegravir-resistant integrase mutants of HIV-1

248th National Meeting (2014)

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