Studies on anti-inflammatory agents. V. Synthesis and pharmacological properties of 3-(difluoromethyl)-1-(4-methoxyphenyl)-5- [4-(methylsulfinyl)phenyl]pyrazole and related compounds.
A series of novel 1,5-diphenylpyrazole derivatives bearing hydrophilic substituents was prepared. The anti-inflammatory and analgesic activities of these compounds were evaluated by using the adjuvant arthritis and Randall-Selitto assays in rats, and the structure-activity relationships were studied. The optimal compound was 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (10) with oral ED50 values of 0.31 and 2.6 mg/kg on adjuvant-induced arthritis and carrageenin-induced foot edema, respectively. Compound 10 showed analgesic activities not only toward inflamed paw but also toward normal paw (ED30 = 0.55 and 1.8 mg/kg, respectively) in the Randall-Selitto assay, and moreover, 10 was effective in the tail-pinch assay (ED50 = 21 mg/kg) similarly to morphine. The asymmetric synthesis and pharmacological properties of the enantiomers of 10 are also reported.
Tsuji
K
K
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Konishi
N
N
Spears
G W
GW
Ogino
T
T
Nakamura
K
K
Tojo
T
T
Ochi
T
T
Shimojo
F
F
Senoh
H
H
Matsuo
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D013454:Sulfoxides; C108904:3-(difluoromethyl)-1-(4-methoxyphenyl)-5-(4-(methylsulfinyl)phenyl)pyrazole