1-Methyl and 1-(2-hydroxyalkyl)-5-(3-alkyl/cycloalkyl/phenyl/naphthylureido)-1H-pyrazole-4-carboxylic acid ethyl esters as potent human neutrophil chemotaxis inhibitors

Bioorg Med Chem. 2009 May 1;17(9):3379-87. doi: 10.1016/j.bmc.2009.03.035. Epub 2009 Mar 25.

Abstract

In this paper we report the synthesis and the chemotaxis inhibitory activity of a number of 1H-pyrazole-4-carboxylic acid ethyl esters 2 functionalized in N1 with a methyl group or different hydroxyalkyl chains and in position 5 with a series of 3-substituted urea groups. These compounds were designed as development of previous pyrazole-urea derivatives that resulted potent IL8-induced neutrophil chemotaxis inhibitors in vitro. Most of the new compounds revealed a potent inhibition of both IL8- and fMLP-OMe-stimulated neutrophil chemotaxis. The most active compounds in the fMLP-OMe induced chemotaxis test showed IC(50) in the range 0.19 nM-2 microM; but we observed a very strong inhibition in the IL8-induced chemotaxis test, having the most active compounds IC(50) at pM concentrations. In vivo compounds 2e and 2f, although to a lesser extent, at 50mg/kg os decreased granulocyte infiltration in zymosan-induced peritonitis in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemotaxis, Leukocyte / drug effects*
  • Drug Design
  • Esters / chemical synthesis
  • Esters / chemistry
  • Esters / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Interleukin-8 / antagonists & inhibitors
  • Interleukin-8 / pharmacology
  • Male
  • Mice
  • Molecular Structure
  • N-Formylmethionine Leucyl-Phenylalanine / analogs & derivatives
  • N-Formylmethionine Leucyl-Phenylalanine / antagonists & inhibitors
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neutrophils / cytology
  • Neutrophils / drug effects*
  • Protein Binding
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Esters
  • Interleukin-8
  • Pyrazoles
  • N-Formylmethionine Leucyl-Phenylalanine
  • formylmethionyl-leucyl-phenylalanine methyl ester