Studies on anti-inflammatory agents. IV. Synthesis and pharmacological properties of 1,5-diarylpyrazoles and related derivatives.
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.
Tsuji
K
K
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka Japan.
Nakamura
K
K
Konishi
N
N
Tojo
T
T
Ochi
T
T
Senoh
H
H
Matsuo
M
M
D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008956:Models, Chemical; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
D000813:Anilides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; C085566:FK 3311; C064874:DuP 697; D007213:Indomethacin