STUDIES ON ANTIINFLAMMATORY AGENTS .4. SYNTHESIS AND PHARMACOLOGICAL PROPERTIES OF 1,5-DIARYLPYRAZOLES AND RELATED DERIVATIVES

A series of novel 1,5-diarylpyrazole derivatives was synthesized and t ested for anti-inflammatory and analgesic activities to develop anti-i nflammatory agents with fewer side effects than existing nonsteroidal anti-inflammatory drugs, The structure-activity relationships in this series were extensively studied. Electron-withdrawing substituents suc h as CN and CF3 were optimal at the 3-position of the pyrazole ring, R eplacement of these substituents with bulky ones gave less active comp ounds. The 4-(methylsulfonyl)phenyl group seemed to be the optimal gro up at the 5-position of the pyrazole ring. The most potent compound wa s 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]- pyrazole-3-carbonit rile (19a), with oral ED50 values 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-Se litto) assay. Compound 19a also showed potent inducible cyclooxygenase (COX-2)-inhibitory activity (IC50 = 0.24 mu m) with no COX-1 inhibiti on even at 100 mu m.