Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase

Bioorg Med Chem Lett. 2015 Sep 15;25(18):3788-92. doi: 10.1016/j.bmcl.2015.07.091. Epub 2015 Jul 30.

Abstract

A series of structure based drug design hypotheses and focused screening efforts led to the identification of tetrahydropyrrolo-diazepenones with striking potency against ERK2 kinase. The role of fluorination in mitigating microsomal clearance was systematically explored. Ultimately, it was found that fluorination of a cyclopentanol substructure provided significant improvement in both potency and human metabolic stability.

Keywords: ATP binding cleft; ERK2 kinase; Extraction ratio; Lower-hinge lysine; Structure based drug design.

MeSH terms

  • Azepines / chemistry
  • Azepines / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Azepines
  • Heterocyclic Compounds, 2-Ring
  • Protein Kinase Inhibitors
  • Pyrroles
  • Mitogen-Activated Protein Kinase 1