Conversion of carbazole carboxamide based reversible inhibitors of Bruton's tyrosine kinase (BTK) into potent, selective irreversible inhibitors in the carbazole, tetrahydrocarbazole, and a new 2,3-dimethylindole series

Bioorg Med Chem Lett. 2018 Oct 1;28(18):3080-3084. doi: 10.1016/j.bmcl.2018.07.041. Epub 2018 Jul 30.

Abstract

Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.

Keywords: BTK; Bruton’s tyrosine kinase; Carbazole; Indole carboxamide; Irreversible inhibitor.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • Carbazoles / chemical synthesis
  • Carbazoles / chemistry
  • Carbazoles / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Carbazoles
  • Indoles
  • Protein Kinase Inhibitors
  • 2,3-dimethylindole
  • Agammaglobulinaemia Tyrosine Kinase