title: 4-amino-1-hydroxy-2-oxo-1,8-naphthyridine-containing compounds having high potency against raltegravir-resistant integrase mutants of HIV-1.
abstract: There are currently three HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) approved by the FDA for the treatment of AIDS. However, the emergence of drug-resistant mutants emphasizes the need to develop additional agents that have improved efficacies against the existent resistant mutants. As reported herein, we modified our recently disclosed 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN inhibitors to develop compounds that have improved 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 in a single round replication assay and have improved potency against vectors harboring the major forms of drug resistant IN mutants. These compounds also have low toxicity for cultured cells, which in several cases, results in selectivity indices (CC50/EC50) of greater than 10000. The compounds have the potential, with additional structural modifications, to yield clinical agents that are effective against the known strains of resistant viruses.
authors.affiliation: Chemical Biology Laboratory, and ‡HIV Drug Resistance Program, Center for Cancer Research, NCI at Frederick, National Institutes of Health , Building 376, Boyles Street, P.O. Box B, Frederick, Maryland 21702, United States.
authors.forename: Xue Zhi
authors.initials: XZ
authors.lastname: Zhao
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Smith
authors.forename: Mathieu
authors.initials: M
authors.lastname: Métifiot
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Paul L
authors.initials: PL
authors.lastname: Boyer
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral; D057809:HEK293 Cells; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D009154:Mutation; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019428:HIV Integrase Inhibitors; D009287:Naphthyridines; D011760:Pyrrolidinones; D011994:Recombinant Proteins; D000068898:Raltegravir Potassium; D019427:HIV Integrase