Discovery of N-substituted 7-azaindoles as Pan-PIM kinase inhibitors - Lead series identification - Part II

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4735-4740. doi: 10.1016/j.bmcl.2017.08.068. Epub 2017 Sep 9.

Abstract

N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate.

Keywords: AML; Cancer; Hit-to-Lead; PK/PD; Pan-PIM kinases; Small molecule inhibitor; X-ray crystallography.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Half-Life
  • Humans
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-pim-1 / chemistry
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • Rats
  • Structure-Activity Relationship

Substances

  • 7-azaindole dimer
  • Indoles
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim