Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation

Bioorg Med Chem Lett. 2020 Jul 1;30(13):127197. doi: 10.1016/j.bmcl.2020.127197. Epub 2020 Apr 15.

Abstract

A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.

Keywords: 2C4 cells; HDAC inhibitor; HDACs 1, 2, 3; HDACs 6, 8; HIV latency; HIV latency reversing agent; Shock and kill; Zinc binding group.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Cell Line, Tumor
  • Dogs
  • HIV-1 / drug effects*
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / pharmacokinetics
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Ketones / chemical synthesis
  • Ketones / pharmacokinetics
  • Ketones / pharmacology*
  • Microbial Sensitivity Tests
  • Rats
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology
  • Virus Activation / drug effects*
  • Virus Latency / drug effects*

Substances

  • Anti-HIV Agents
  • Histone Deacetylase Inhibitors
  • Ketones
  • Spiro Compounds