A potent seven-membered cyclic BTK (Bruton's tyrosine Kinase) chiral inhibitor conceived by structure-based drug design to lock its bioactive conformation

Bioorg Med Chem Lett. 2019 May 1;29(9):1074-1078. doi: 10.1016/j.bmcl.2019.03.001. Epub 2019 Mar 6.

Abstract

A seven-membered cyclic chiral analog of potent lead BTK inhibitor 1 was envisioned by structure-based design to lock the molecule into its bioactive conformation. For the elaboration of the seven-membered ring, compound 1 pyridone 6-position was substituted with the purpose to prevent formation of reactive metabolites. Eventually, the cyclic chiral compound 3 maintained the high potency of 1, and most importantly showed no activity at either GSH or TDI assays suggesting no formation of reactive metabolites. The anticipated bound conformation of 3 to BTK was confirmed by X-ray crystallography. Synthetically, the crucial seven-membered ring formation was obtained by using TosMIC as a connective reagent.

Keywords: Bioactive conformation; Bruton’s tyrosine kinase; Reactive metabolite; Seven-membered BTK inhibitor; TosMIC as connective reagent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • Humans
  • Molecular Conformation
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Structure, Tertiary
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human