Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor

Bioorg Med Chem Lett. 2019 Jan 1;29(1):83-88. doi: 10.1016/j.bmcl.2018.11.009. Epub 2018 Nov 13.

Abstract

We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.

Keywords: CHDI-390576; CNS-penetrant; Class IIa HDAC inhibitor; HDAC4 inhibition; Hydroxamic acid.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Mice
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Histone Deacetylases