Synthesis and biological evaluation of 5-[[3,5-bis(1,1-dimethylethyl)- 4-hydroxyphenyl]methylene]oxazoles, -thiazoles, and -imidazoles: novel dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatory activity. 1994

P C Unangst, and D T Connor, and W A Cetenko, and R J Sorenson, and C R Kostlan, and J C Sircar, and C D Wright, and D J Schrier, and R D Dyer
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.

A variety of benzylideneoxazoles, -thiazoles, and -imidazoles derived from 2,6-di-tert-butylphenol were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. The target compounds exhibit varying degrees of selectivity toward the two enzymes. Several compounds are orally active in the rat carageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models. Structure-activity relationships are discussed. From this work, (Z)-5-[[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]-methylene]-2-imino-4-thiazolidinone methanesulfonate salt (CI-1004) was identified as a potent dual inhibitor of 5-lipoxygenase (IC50 = 0.77 microM) and cyclooxygenase (IC50 = 0.39 microM), with oral activity (ID40 = 0.6 mg/kg) in the rat MFE model of inflammation.

UI MeSH Term Description Entries
D007093 Imidazoles Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D010080 Oxazoles Five-membered heterocyclic ring structures containing an oxygen in the 1-position and a nitrogen in the 3-position, in distinction from ISOXAZOLES where they are at the 1,2 positions. Oxazole,1,3-Oxazolium-5-Oxides,Munchnones,1,3 Oxazolium 5 Oxides
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000894 Anti-Inflammatory Agents, Non-Steroidal Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects. Analgesics, Anti-Inflammatory,Aspirin-Like Agent,Aspirin-Like Agents,NSAID,Non-Steroidal Anti-Inflammatory Agent,Non-Steroidal Anti-Inflammatory Agents,Nonsteroidal Anti-Inflammatory Agent,Anti Inflammatory Agents, Nonsteroidal,Antiinflammatory Agents, Non Steroidal,Antiinflammatory Agents, Nonsteroidal,NSAIDs,Nonsteroidal Anti-Inflammatory Agents,Agent, Aspirin-Like,Agent, Non-Steroidal Anti-Inflammatory,Agent, Nonsteroidal Anti-Inflammatory,Anti-Inflammatory Agent, Non-Steroidal,Anti-Inflammatory Agent, Nonsteroidal,Anti-Inflammatory Analgesics,Aspirin Like Agent,Aspirin Like Agents,Non Steroidal Anti Inflammatory Agent,Non Steroidal Anti Inflammatory Agents,Nonsteroidal Anti Inflammatory Agent,Nonsteroidal Anti Inflammatory Agents,Nonsteroidal Antiinflammatory Agents
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013844 Thiazoles Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms. Thiazole
D014407 Tumor Cells, Cultured Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely. Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D016859 Lipoxygenase Inhibitors Compounds that bind to and inhibit that enzymatic activity of LIPOXYGENASES. Included under this category are inhibitors that are specific for lipoxygenase subtypes and act to reduce the production of LEUKOTRIENES. 5-Lipoxygenase Inhibitor,Lipoxygenase Inhibitor,12-Lipoxygenase Inhibitors,15-Lipoxygenase Inhibitors,5-Lipoxygenase Inhibitors,Arachidonate 12-Lipoxygenase Inhibitors,Arachidonate 15-Lipoxygenase Inhibitors,Arachidonate 5-Lipoxygenase Inhibitors,Inhibitors, Lipoxygenase,12 Lipoxygenase Inhibitors,12-Lipoxygenase Inhibitors, Arachidonate,15 Lipoxygenase Inhibitors,15-Lipoxygenase Inhibitors, Arachidonate,5 Lipoxygenase Inhibitor,5 Lipoxygenase Inhibitors,5-Lipoxygenase Inhibitors, Arachidonate,Arachidonate 12 Lipoxygenase Inhibitors,Arachidonate 15 Lipoxygenase Inhibitors,Arachidonate 5 Lipoxygenase Inhibitors,Inhibitor, 5-Lipoxygenase,Inhibitor, Lipoxygenase,Inhibitors, 12-Lipoxygenase,Inhibitors, 15-Lipoxygenase,Inhibitors, 5-Lipoxygenase,Inhibitors, Arachidonate 12-Lipoxygenase,Inhibitors, Arachidonate 15-Lipoxygenase,Inhibitors, Arachidonate 5-Lipoxygenase
D016861 Cyclooxygenase Inhibitors Compounds or agents that combine with cyclooxygenase (PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES) and thereby prevent its substrate-enzyme combination with arachidonic acid and the formation of eicosanoids, prostaglandins, and thromboxanes. Cyclo-Oxygenase Inhibitor,Cyclooxygenase Inhibitor,Prostaglandin Endoperoxide Synthase Inhibitor,Prostaglandin Endoperoxide Synthase Inhibitors,Prostaglandin Synthase Inhibitor,Prostaglandin Synthase Inhibitors,Prostaglandin Synthesis Antagonist,Prostaglandin Synthesis Antagonists,Cyclo-Oxygenase Inhibitors,Inhibitors, Cyclo-Oxygenase,Inhibitors, Cyclooxygenase,Inhibitors, Prostaglandin Synthase,Inhibitors, Prostaglandin-Endoperoxide Synthase,Antagonist, Prostaglandin Synthesis,Antagonists, Prostaglandin Synthesis,Cyclo Oxygenase Inhibitor,Cyclo Oxygenase Inhibitors,Inhibitor, Cyclo-Oxygenase,Inhibitor, Cyclooxygenase,Inhibitor, Prostaglandin Synthase,Inhibitors, Cyclo Oxygenase,Inhibitors, Prostaglandin Endoperoxide Synthase,Synthase Inhibitor, Prostaglandin,Synthesis Antagonist, Prostaglandin
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus

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