Indole RSK Inhibitors. Part 1: Discovery and Initial SAR

Bioorg Med Chem Lett. 2012 Jan 1;22(1):733-7. doi: 10.1016/j.bmcl.2011.10.030. Epub 2011 Oct 14.

Abstract

A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were identified through high throughput screening. An RSK crystal structure and exploratory SAR were used to define the series pharmacophore. Compounds with good cell potency, such as compounds 43, 44, and 55 were identified, and form the basis for subsequent kinase selectivity optimization.

MeSH terms

  • Amides / chemistry
  • Azepines / chemical synthesis*
  • Azepines / pharmacology
  • Chemistry, Pharmaceutical / methods
  • Crystallography, X-Ray / methods
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Models, Chemical
  • Molecular Conformation
  • Nitrogen / chemistry
  • Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors*
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Structure-Activity Relationship

Substances

  • 1-oxo-2,3,4,5-tetrahydro-1H-(1,4)diazepino(1,2-a)indole-8-carboxamide
  • Amides
  • Azepines
  • Enzyme Inhibitors
  • Indoles
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Nitrogen