Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3939-3943. doi: 10.1016/j.bmcl.2017.03.040. Epub 2017 Mar 18.

Abstract

8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.

Keywords: ATP ribose pocket; BTK inhibitor; Immunology; Kinase selectivity; Rheumatoid arthritis.

MeSH terms

  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Models, Molecular
  • Molecular Structure
  • Morpholines / chemical synthesis
  • Morpholines / chemistry
  • Morpholines / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship
  • Transcriptional Regulator ERG / antagonists & inhibitors
  • Transcriptional Regulator ERG / metabolism

Substances

  • 3-morpholino-imidazole(1,5-a)pyrazine
  • ERG protein, human
  • Imidazoles
  • Morpholines
  • Protein Kinase Inhibitors
  • Transcriptional Regulator ERG
  • Protein-Tyrosine Kinases