Development of a selective HDAC inhibitor aimed at reactivating the HIV latent reservoir

Bioorg Med Chem Lett. 2020 Sep 1;30(17):127367. doi: 10.1016/j.bmcl.2020.127367. Epub 2020 Jun 26.

Abstract

The synthesis and SAR development of a trisubstituted imidazole HDAC inhibitor is described. The compounds were synthesized with high diastereocontrol by leveraging Ellman sulfinyl imine chemistry. Structural elucidation provided insight into binding mode and supported design rational. Pharmacokinetic properties of lead compounds were determined.

Keywords: HDAC; HIV; Latent reservoir; Medicinal chemistry; SAR analysis; X-ray structure.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / virology
  • Crystallography, X-Ray
  • HIV-1 / drug effects
  • HIV-1 / physiology
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism*
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Imidazoles / pharmacology
  • Inhibitory Concentration 50
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Rats
  • Structure-Activity Relationship

Substances

  • Histone Deacetylase Inhibitors
  • Imidazoles
  • Isoenzymes
  • imidazole
  • Histone Deacetylases