Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold

Bioorg Med Chem. 2015 Feb 15;23(4):891-901. doi: 10.1016/j.bmc.2014.10.043. Epub 2014 Nov 6.

Abstract

A series of novel reversible BTK inhibitors was designed based on the structure of the recently reported preclinical drug RN486. Knowledge of the binding mode of RN486 led to the design of new inhibitors that utilized pyrrolo[2,3-d]pyrimidine to conformationally restrain key pharmacophoric groups within the molecule. Comprehensive SAR was disclosed and the most promising compound 4x displayed superior activity both in BTK enzyme (IC50=4.8nM) and cellular inhibition (IC50=17nM) assays to that of RN486.

Keywords: BTK inhibitors; Pyrrolo[23-d]pyrimidine; SAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Humans
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • pyrimidine