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

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.