Discovery and evaluation of 1H-pyrrolo[2,3-b]pyridine based selective and reversible small molecule BTK inhibitors for the treatment of rheumatoid arthritis

Bioorg Med Chem Lett. 2017 Apr 15;27(8):1867-1873. doi: 10.1016/j.bmcl.2017.02.026. Epub 2017 Feb 22.

Abstract

In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA.

Keywords: 1H-Pyrrolo[2,3-b]pyridine; Autoimmune diseases; BTK; Human whole blood; Kinase selectivity; Reversible; Rheumatoid arthritis.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Antirheumatic Agents / chemistry*
  • Antirheumatic Agents / pharmacokinetics
  • Antirheumatic Agents / pharmacology
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / enzymology
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Pyrroles / chemistry*
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use*
  • Structure-Activity Relationship

Substances

  • Antirheumatic Agents
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrroles
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • pyrrolo(2, 3-b)pyridine