Bicyclic 1‑Hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide-Containing HIV‑1 Integrase Inhibitors Having High Antiviral Potency against Cells Harboring Raltegravir-Resistant Integrase Mutants

• Published in: Journal of medicinal chemistry 2014-02, Vol.57 (4), p.1573-1582
• Main Authors: Zhao, Xue Zhi, Smith, Steven J, Métifiot, Mathieu, Johnson, Barry C, Marchand, Christophe, Pommier, Yves, Hughes, Stephen H, Burke, Terrence R
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Cell Line; Drug Resistance, Viral; HIV Integrase - genetics; HIV-1 - drug effects; Human immunodeficiency virus 1; Humans; Magnetic Resonance Spectroscopy; Mutation; Pyridines - chemistry; Pyridines - pharmacology; Pyrrolidinones - pharmacology; Raltegravir Potassium; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401902n

Integrase (IN) inhibitors are the newest class of antiretroviral agents developed for the treatment of HIV-1 infections. 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 that will have greater efficacy against RAL- and EVG-resistant strains of IN. The FDA has recently approved the first second generation INSTI, GSK’s Dolutegravir (DTG) (August 2013). Our current article describes the design, synthesis, and evaluation of a series of 1,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, 1,4-dihydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides, and 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides. This resulted in the identification of noncytotoxic inhibitors that exhibited single digit nanomolar EC50 values against HIV-1 vectors harboring wild-type IN in cell-based assays. Importantly, some of these new inhibitors retain greater antiviral efficacy compared to that of RAL when tested against a panel of IN mutants that included Y143R, N155H, G140S/Q148H, G118R, and E138K/Q148K.