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.
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.
Chemical Biology Laboratory, National Cancer Institute-Frederick, National Institutes of Health , Frederick, Maryland 21702, United States.
Xue Zhi
XZ
Zhao
Steven J
SJ
Smith
Mathieu
M
Métifiot
Barry C
BC
Johnson
Christophe
C
Marchand
Yves
Y
Pommier
Stephen H
SH
Hughes
Terrence R
TR
Burke
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D021241:Spectrometry, Mass, Electrospray Ionization
D019380:Anti-HIV Agents; D011725:Pyridines; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C023666:pyridine