Tetrasubstituted imidazole inhibitors of cytokine release: probing substituents in the N-1 position

J Med Chem. 2004 Dec 2;47(25):6311-25. doi: 10.1021/jm0496584.

Abstract

We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory activity by using our previously described regiospecific synthesis. Systematic optimization of the imidazole N-1 substituent resulted in compound 9b that potently inhibited the mitogen-activated protein kinase p38 (p38 IC(50) = 0.218 microM) as well as the release of the proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) from human whole blood after stimulation with LPS. Furthermore, compound 9b exhibited reduced cytochrome P450 interaction in comparison with SB203580. This result is particularly important, since cytochrome P450 interaction is observed for some p38 inhibitors and in turn can potentially cause drug-drug interaction or lead to other hepatic changes such as P450 enzyme induction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemical synthesis*
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Binding Sites
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytokines / antagonists & inhibitors*
  • Cytokines / blood
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / blood
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Models, Molecular
  • Molecular Conformation
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / chemistry

Substances

  • Aminopyridines
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytokines
  • Imidazoles
  • Interleukin-1
  • Isoenzymes
  • N-(4-(5-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methylsulfanyl-3H-imidazol-4-yl)pyridin-2-yl)acetamide
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Cytochrome P-450 Enzyme System
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580