Novel 1,2,4-oxadiazoles and 1,2,4-thiadiazoles as Dual 5-lipoxygenase and Cyclooxygenase Inhibitors

J Med Chem. 1992 Oct 2;35(20):3691-8. doi: 10.1021/jm00098a015.

Abstract

A series of 1,2,4-oxadiazoles and 1,2,4-thiadiazoles containing a 2,6-di-tert-butylphenol substituent were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. Several of these compounds show oral efficacy in the rat carrageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models, without concomitant gastric ulceration. Structure-activity relationships are discussed. The best compounds (ID40 values in MFE of 3-8 mg/kg po) contain guanidine-derived substituents on the heterocyclic ring.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors*
  • Male
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / pharmacology
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Thiadiazoles / chemical synthesis*
  • Thiadiazoles / pharmacology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism

Substances

  • Anti-Inflammatory Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase Inhibitors
  • Enzyme Inhibitors
  • Lipoxygenase Inhibitors
  • Oxadiazoles
  • Thiadiazoles