Design, synthesis and evaluation of novel 5-phenylpyridin-2(1H)-one derivatives as potent reversible Bruton's tyrosine kinase inhibitors

Bioorg Med Chem. 2015 Jan 15;23(2):348-64. doi: 10.1016/j.bmc.2014.11.006. Epub 2014 Nov 10.

Abstract

A series of novel reversible Btk inhibitors has been designed based on the structure of the recently reported preclinical drug RN486. The synthesis and SAR of these compounds are described. Among these derivatives, compound 16b was identified to be a potent and orally available reversible agent with satisfactory Btk enzymatic and cellular inhibition in vitro, as well as favorable PK properties and inhibition of arthritis in vivo.

Keywords: Efficacy; In vivo; Reversible Btk inhibitors; SAR; Structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Arthritis, Rheumatoid / chemically induced
  • Arthritis, Rheumatoid / drug therapy
  • Binding Sites
  • Cell Line
  • Drug Design*
  • Female
  • Half-Life
  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacokinetics
  • Isoquinolines / pharmacology
  • Male
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyridones / chemistry*
  • Pyridones / pharmacokinetics
  • Pyridones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Structure-Activity Relationship

Substances

  • 6-cyclopropyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)isoquinolin-1(2H)-one
  • Isoquinolines
  • Protein Kinase Inhibitors
  • Pyridones
  • RN486
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human