title: IDX-899, an aryl phosphinate-indole non-nucleoside reverse transcriptase inhibitor for the potential treatment of HIV infection.
abstract: Antiretroviral drug resistance is one of the complications of highly active antiretroviral therapy (HAART). Second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) are being developed for use in patients infected with HIV-1 because of the enhanced activity of these inhibitors against viruses that are resistant to the first-generation NNRTIs. IDX-899 (GSK-2248761), under development by Idenix Pharmaceuticals Inc and ViiV Healthcare, is an aryl phosphinate-indole second-generation NNRTI that potently and selectively inhibits wild-type and NNRTI-resistant HIV-1 in vitro. Preclinical data for IDX-899 suggest a significantly greater barrier to resistance compared with that of the first-generation NNRTI efavirenz. Two pathways of resistance have been identified for IDX-899 in vitro that include Glu138Lys and Val90Ile/Tyr181Cys mutations. Pharmacokinetic studies demonstrated that IDX-899 exhibits linear, dose-proportional and food-dependent pharmacokinetics; Cmin concentrations achieved with this drug allow once-daily dosing. In phase I clinical trials, IDX-899 reduced HIV-1 RNA and increased CD4+ cell counts in treatment-naïve patients infected with HIV-1. At the time of publication, a phase II clinical trial of IDX-899 was being conducted.
authors.affiliation: Wingate University School of Pharmacy, Campus Box 3087, Wingate, NC 28174-0159, USA. o.klibanov@wingate.edu
authors.forename: Olga M
authors.initials: OM
authors.lastname: Klibanov
authors.forename: Roberta L
authors.initials: RL
authors.lastname: Kaczor
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects / Q000379:methods; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010721:Phosphinic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; C534138:IDX 899; D007211:Indoles; D010721:Phosphinic Acids; D018894:Reverse Transcriptase Inhibitors