Novel JAK1-selective benzimidazole inhibitors with enhanced membrane permeability

Bioorg Med Chem Lett. 2016 Jul 15;26(14):3213-3215. doi: 10.1016/j.bmcl.2016.05.078. Epub 2016 May 27.

Abstract

The previously identified Janus kinase 1 (JAK1)-selective inhibitor, 1-(2-aminoethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide (2), suffered from low cell permeability, which resulted in poor pharmacokinetic properties. In this study, by introducing less polar hydrogen bond donors at N(1) (a hydroxyalkyl or a methylaminoalkyl group) and C2 (a cyclohexanol group) positions, a series of novel benzimidazole derivatives were prepared, which exhibited selective JAK1 inhibitory activity (IC50 against JAK1=0.08-0.15μM; JAK1-selectivity=26-40 fold vs JAK2, 12-23 fold vs JAK3, and 38-54 fold vs Tyk2) along with significantly increased lipophilicity (3.3-15.8 times) as well as membrane permeability (6.3-12 times).

Keywords: Benzimidazole; Janus kinase; Rheumatoid arthritis; Selective inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Cell Membrane Permeability / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / metabolism
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Isoenzymes
  • Protein Kinase Inhibitors
  • benzimidazole
  • JAK1 protein, human
  • Janus Kinase 1