GRL-04810 and GRL-05010, difluoride-containing nonpeptidic HIV-1 protease inhibitors (PIs) that inhibit the replication of multi-PI-resistant HIV-1 in vitro and possess favorable lipophilicity that may allow blood-brain barrier penetration

Antimicrob Agents Chemother. 2013 Dec;57(12):6110-21. doi: 10.1128/AAC.01420-13. Epub 2013 Sep 30.

Abstract

We designed, synthesized, and identified two novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-04810 and GRL-05010, containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, bis-tetrahydrofuranylurethane (bis-THF), and a difluoride moiety, both of which are active against the laboratory strain HIV-1LAI (50% effective concentrations [EC50s], 0.0008 and 0.003 μM, respectively) with minimal cytotoxicity (50% cytotoxic concentrations [CC50s], 17.5 and 37.0 μM, respectively, in CD4(+) MT-2 cells). The two compounds were active against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to various antiviral regimens. GRL-04810 and GRL-05010 also blocked the infectivity and replication of each of the HIV-1NL4-3 variants selected by up to 5 μM lopinavir (EC50s, 0.03 and 0.03 μM, respectively) and atazanavir (EC50s, 0.02 and 0.04 μM, respectively). Moreover, they were active against darunavir (DRV)-resistant variants (EC50 in 0.03 to 0.034 μM range for GRL-04810 and 0.026 to 0.043 μM for GRL-05010), while DRV had EC50s between 0.02 and 0.174 μM. GRL-04810 had a favorable lipophilicity profile as determined with the partition (log P) and distribution (log D) coefficients of -0.14 and -0.29, respectively. The in vitro blood-brain barrier (BBB) permeability assay revealed that GRL-04810 and GRL-05010 may have a greater advantage in terms of crossing the BBB than the currently available PIs, with apparent penetration indexes of 47.8 × 10(-6) and 61.8 × 10(-6) cm/s, respectively. The present data demonstrate that GRL-04810 and GRL-05010 exert efficient activity against a wide spectrum of HIV-1 variants in vitro and suggest that two fluorine atoms added to their bis-THF moieties may well enhance their penetration across the BBB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Atazanavir Sulfate
  • Blood-Brain Barrier / drug effects
  • Carbamates / chemistry
  • Carbamates / pharmacology*
  • Cell Line
  • Darunavir
  • Drug Resistance, Multiple, Viral
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Fluorides / chemistry
  • HIV Protease / chemistry
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / growth & development
  • Haplorhini
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Lopinavir / pharmacology
  • Models, Biological
  • Molecular Docking Simulation
  • Oligopeptides / pharmacology
  • Pericytes / cytology
  • Pericytes / drug effects
  • Pericytes / metabolism
  • Pyridines / pharmacology
  • Rats
  • Saquinavir / pharmacology
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / virology
  • Virus Replication / drug effects*

Substances

  • Carbamates
  • GRL-04810
  • GRL-05010
  • HIV Protease Inhibitors
  • Oligopeptides
  • Pyridines
  • Sulfonamides
  • Lopinavir
  • Atazanavir Sulfate
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1
  • Saquinavir
  • Fluorides
  • Darunavir