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: Olga M Klibanov, Roberta L Kaczor
• Journal: Current opinion in investigational drugs (London, England : 2000) (Curr Opin Investig Drugs) Vol. 11 Issue 2 Pg. 237-45 (Feb 2010) ISSN: 2040-3429 [Electronic] England
• PMID: 20112173 (Publication Type: Journal Article, Review)

Chemical References

• Anti-HIV Agents
• IDX 899
• Indoles
• Phosphinic Acids
• Reverse Transcriptase Inhibitors

Topics

• Animals
• Anti-HIV Agents (pharmacokinetics, pharmacology, therapeutic use)
• Antiretroviral Therapy, Highly Active (adverse effects, methods)
• Clinical Trials as Topic
• Drug Evaluation, Preclinical
• Drug Resistance, Viral
• HIV Infections (drug therapy, virology)
• HIV-1 (drug effects)
• Humans
• Indoles (pharmacokinetics, pharmacology, therapeutic use)
• Phosphinic Acids (pharmacokinetics, pharmacology, therapeutic use)
• Reverse Transcriptase Inhibitors (pharmacokinetics, pharmacology, therapeutic use)