Design and synthesis of piperazine-indole p38 alpha MAP kinase inhibitors with improved pharmacokinetic profiles

Bioorg Med Chem Lett. 2010 Feb 1;20(3):828-31. doi: 10.1016/j.bmcl.2009.12.091. Epub 2010 Jan 4.

Abstract

Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38alpha MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Dogs
  • Drug Design*
  • Haplorhini
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacokinetics
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Piperazine
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Structure, Secondary
  • Rats

Substances

  • Indoles
  • Piperazines
  • Protein Kinase Inhibitors
  • Piperazine
  • Mitogen-Activated Protein Kinase 14