Design, synthesis, and preliminary pharmacological evaluation of N-acyl-3-aminoglutarimides as broad-spectrum chemokine inhibitors in vitro and anti-inflammatory agents in vivo

J Med Chem. 2002 Jan 17;45(2):360-70. doi: 10.1021/jm010984i.

Abstract

A series of N-substituted 3-aminoglutarimides have been synthesized and tested for inhibitory activity against a range of chemokines in vitro and for suppression of lipopolysaccharide-induced inflammation in vivo. The results show that they represent the first class of small molecules with broad-spectrum chemokine inhibitory effects. Among the compounds studied, 10 (NR58,4) was the most potent, being active at doses between 5 and 15 nM in vitro and at 0.3 mg kg(-1) in vivo.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cell Line
  • Chemokine CCL2 / chemistry*
  • Chemokine CCL2 / pharmacology
  • Chemokines / antagonists & inhibitors*
  • Chemotaxis, Leukocyte / drug effects
  • Humans
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Molecular Mimicry
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Piperidones / chemical synthesis*
  • Piperidones / chemistry
  • Piperidones / pharmacology
  • Receptors, Chemokine / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • 3-(undec-10-enoylamino)glutarimide
  • Anti-Inflammatory Agents, Non-Steroidal
  • Chemokine CCL2
  • Chemokines
  • Lipopolysaccharides
  • Oligopeptides
  • Peptide Fragments
  • Piperidones
  • Receptors, Chemokine
  • Tumor Necrosis Factor-alpha