Development of methyl isoxazoleazepines as inhibitors of BET

Bioorg Med Chem Lett. 2015 May 1;25(9):1842-8. doi: 10.1016/j.bmcl.2015.03.045. Epub 2015 Mar 24.

Abstract

In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model.

Keywords: BET inhibitors; Bromodomains; Isoxazoles; MYC; Unbound clearance.

MeSH terms

  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Cell Cycle Proteins
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors*
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • RNA-Binding Proteins / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*

Substances

  • Azepines
  • BRD2 protein, human
  • BRD3 protein, human
  • BRD4 protein, human
  • BRDT protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Oxazoles
  • RNA-Binding Proteins
  • Transcription Factors
  • methyl isoxazoleazepine
  • Protein Serine-Threonine Kinases