Novel antiarthritic agents with 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) skeleton: cytokine suppressive dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase.
Various 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the gamma-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1, 2-isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate and is now under clinical trials. The structure-activity relationships (SAR) examined and some pharmacological evaluations are described.
Inagaki
M
M
Shionogi Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, Japan.
Tsuri
T
T
Jyoyama
H
H
Ono
T
T
Yamada
K
K
Kobayashi
M
M
Hori
Y
Y
Arimura
A
A
Yasui
K
K
Ohno
K
K
Kakudo
S
S
Koizumi
K
K
Suzuki
R
R
Kawai
S
S
Kato
M
M
Matsumoto
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy*; D001169:Arthritis, Experimental / Q000188:drug therapy; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003499:Cyclic S-Oxides / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use
C409872:((E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)- 2-ethyl-1,2-isothiazolidine-1,1-dioxide); D000894:Anti-Inflammatory Agents, Non-Steroidal; D003499:Cyclic S-Oxides; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D013844:Thiazoles; D007975:Leukotriene B4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone