Optimization of 5-vinylaryl-3-pyridinecarbonitriles as PKCtheta inhibitors

Bioorg Med Chem Lett. 2010 Mar 15;20(6):1965-8. doi: 10.1016/j.bmcl.2010.01.119. Epub 2010 Jan 28.

Abstract

Analog 8, a 3-pyridinecarbonitrile with an (E)-2-[6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl]vinyl group at C-5, had an IC(50) value of 1.1 nM for the inhibition of PKCtheta and potently blocked the production of IL-2 in both stimulated murine T cells (IC(50)=34 nM) and human whole blood (IC(50)=500 nM).

MeSH terms

  • Animals
  • Humans
  • Interleukin-2 / biosynthesis
  • Isoenzymes / antagonists & inhibitors*
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Nitriles / chemistry
  • Nitriles / pharmacology*
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C-theta
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism

Substances

  • Interleukin-2
  • Isoenzymes
  • Nitriles
  • Protein Kinase Inhibitors
  • Prkcq protein, mouse
  • Protein Kinase C
  • Protein Kinase C-theta