Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127531. doi: 10.1016/j.bmcl.2020.127531. Epub 2020 Sep 2.


Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.

Keywords: ALLINI; HIV-1 integrase; Inhibitor; LEDGF/p75; Macrocycle; PXR.

MeSH terms

  • Allosteric Regulation / drug effects
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • HIV Integrase Inhibitors / chemical synthesis
  • HIV Integrase Inhibitors / chemistry
  • HIV Integrase Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • Humans
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Pregnane X Receptor / antagonists & inhibitors*
  • Pregnane X Receptor / metabolism
  • Structure-Activity Relationship
  • Virus Replication / drug effects


  • Anti-HIV Agents
  • HIV Integrase Inhibitors
  • Macrocyclic Compounds
  • Pregnane X Receptor