Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors

Bioorg Med Chem. 2021 Jun 15:40:116163. doi: 10.1016/j.bmc.2021.116163. Epub 2021 Apr 20.

Abstract

Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4,5-b]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. From a starting hit molecule 1, medicinal chemistry optimization led to the development of a lead compound 30, which exhibited 58 nM BTK inhibitory potency in human whole blood and high kinome selectivity. Additionally, the compound demonstrated favorable pharmacokinetics (PK), and showed potent dose-dependent efficacy in a rat CIA model.

Keywords: Bruton’s tyrosine kinase; H3 selectivity pocket; Reversible BTK inhibitor; Selective.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridines
  • imidazo(4,5-b)pyridine
  • Agammaglobulinaemia Tyrosine Kinase