Abstract
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.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / adverse effects
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Arthritis / drug therapy*
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Arthritis, Experimental / drug therapy
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Cyclic S-Oxides / adverse effects
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Cyclic S-Oxides / chemical synthesis*
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Cyclic S-Oxides / therapeutic use
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / chemical synthesis
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Cyclooxygenase Inhibitors / therapeutic use
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Dinoprostone / antagonists & inhibitors
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Dinoprostone / biosynthesis
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Edema / chemically induced
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Edema / drug therapy
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Female
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Gastric Mucosa / drug effects
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Humans
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / pharmacology
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Isoenzymes / pharmacology*
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Leukotriene B4 / antagonists & inhibitors
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Leukotriene B4 / biosynthesis
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Lipoxygenase Inhibitors* / chemical synthesis
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Lipoxygenase Inhibitors* / therapeutic use
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Male
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Membrane Proteins
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Prostaglandin-Endoperoxide Synthases / pharmacology*
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Rats
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Rats, Inbred Lew
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Structure-Activity Relationship
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Synovial Membrane / drug effects
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Synovial Membrane / metabolism
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Thiazoles / adverse effects
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Thiazoles / chemical synthesis*
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Thiazoles / therapeutic use
Substances
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((E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)- 2-ethyl-1,2-isothiazolidine-1,1-dioxide)
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclic S-Oxides
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Interleukin-1
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Isoenzymes
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Lipoxygenase Inhibitors
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Membrane Proteins
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Thiazoles
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Leukotriene B4
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone