Pyrrolo[2,3-b]pyridine derivatives as potent Bruton's tyrosine kinase inhibitors

Bioorg Med Chem. 2015 Aug 1;23(15):4344-4353. doi: 10.1016/j.bmc.2015.06.023. Epub 2015 Jun 17.

Abstract

A series of pyrrolo[2,3-b]pyridine-based derivatives were designed as potent Bruton's tyrosine kinase (BTK) inhibitors by using a scaffold-hopping strategy. Structure-activity relationship studies identified five compounds (3n, 3p, 3q, 3r, and 3s) with IC50 of less than 10nM in BTK enzyme assay and five compounds (3m, 3n, 3o, 3p, and 3t) with IC50 of less than 20 nM in Ramos cell assay. As one of the most potent inhibitors, compound 3p exhibited superior activity to that of compound 1 (RN486) and pyrrolo[2,3-d]pyrimidine derivative 2 in both BTK enzymatic (IC50=6.0 nM) and cellular inhibition (IC50=14 nM) assays. In addition, 3p displayed favorable overall pharmacokinetic profiles compared with 1 and 2.

Keywords: BTK kinase; Inhibitor; Pyrrolo[2,3-b]pyridine; SAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Binding Sites
  • Cell Line
  • Half-Life
  • Humans
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyridines
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • pyridine