Studies on anti-inflammatory agents. IV. Synthesis and pharmacological properties of 1,5-diarylpyrazoles and related derivatives

Chem Pharm Bull (Tokyo). 1997 Jun;45(6):987-95. doi: 10.1248/cpb.45.987.

Abstract

A series of novel 1,5-diarylpyrazole derivatives was synthesized and tested for anti-inflammatory and analgesic activities to develop anti-inflammatory agents with fewer side effects than existing nonsteroidal anti-inflammatory drugs. The structure-activity relationships in this series were extensively studied. Electron-withdrawing substituents such as CN and CF3 were optimal at the 3-position of the pyrazole ring. Replacement of these substituents with bulky ones gave less active compounds. The 4-(methylsulfonyl)phenyl group seemed to be the optimal group at the 5-position of the pyrazole ring. The most potent compound was 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyrazole-3-carbonitrile (19a), with oral ED50 value of 0.030 and 0.47 mg/kg on adjuvant-induced arthritis and collagen-induced arthritis, respectively, and an ED30 value of 7.4 mg/kg in the yeast-induced hyperalgesia (Randall-Selitto) assay. Compound 19a also showed potent inducible cyclooxygenase (COX-2)-inhibitory activity (IC50 = 0.24 microM) with no COX-1 inhibition even at 100 microM.

MeSH terms

  • Anilides / chemistry
  • Anilides / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • CHO Cells
  • Cricetinae
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology
  • Indomethacin / pharmacology
  • Male
  • Models, Chemical
  • Models, Molecular
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Thiophenes / chemistry
  • Thiophenes / pharmacology

Substances

  • Anilides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase Inhibitors
  • Pyrazoles
  • Thiophenes
  • FK 3311
  • DuP 697
  • Indomethacin