Novel 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols With Topical Antiinflammatory Activity

J Med Chem. 1992 Aug 21;35(17):3148-55. doi: 10.1021/jm00095a009.

Abstract

The synthesis, biological evaluation, and structure-activity relationships of a series of 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols are described. These compounds show potent dose-dependent topical antiinflammatory activity in murine models of skin inflammation. This effect is likely due to inhibition of cytochrome P450 and consequent reduction in levels of 12R-HETE in the skin. These compounds were examined for their ability to inhibit the oxidative metabolism of arachidonic acid; they specifically inhibit the formation of prostacyclins in mouse macrophages. To study the effects of structure on the in vivo activity, three general features of the molecules were varied: the position of attachment of the pyridine nucleus (A), the second aromatic residue (B), and the nitrogen base on the ethanol chain (C). 1-[4-(4-Pyridyl)phenyl]-1-(4-fluorophenyl)-2- imidazolylethanol (2a, DuP 983) shows a very attractive profile of antiinflammatory activity and has been selected for clinical evaluation as a topical antiinflammatory agent.

MeSH terms

  • Administration, Topical
  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Arachidonic Acid
  • Calcimycin
  • Cyclooxygenase Inhibitors / pharmacology
  • Dermatitis / drug therapy
  • Dermatitis / etiology
  • Edema / chemically induced
  • Edema / drug therapy
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Lipoxygenase Inhibitors / pharmacology
  • Male
  • Mice
  • Molecular Structure
  • Phospholipases A / antagonists & inhibitors
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Structure-Activity Relationship
  • Tetradecanoylphorbol Acetate

Substances

  • 1-(4-(4-pyridyl)phenyl)-1-(4-fluorophenyl)-2-imidazolylethanol
  • Anti-Inflammatory Agents
  • Cyclooxygenase Inhibitors
  • Imidazoles
  • Lipoxygenase Inhibitors
  • Pyridines
  • Arachidonic Acid
  • Calcimycin
  • Phospholipases A
  • Tetradecanoylphorbol Acetate