433217-05-1Relevant academic research and scientific papers
The development of new isoxazolone based inhibitors of tumor necrosis factor-alpha (TNF-α) production
Laughlin, Steven K.,Clark, Michael P.,Djung, Jane F.,Golebiowski, Adam,Brugel, Todd A.,Sabat, Mark,Bookland, Roger G.,Laufersweiler, Matthew J.,VanRens, John C.,Townes, Jennifer A.,De, Biswanath,Hsieh, Lily C.,Xu, Susan C.,Walter, Richard L.,Mekel, Marlene J.,Janusz, Michael J.
, p. 2399 - 2403 (2007/10/03)
4-Aryl-3-pyridyl and 4-aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-α) inhibitors, which contain a novel isoxazolone five-membered heterocyclic core are described. Many showed sub-micromolar activity against lipopolysaccharide-induced TNF-α production.
The development of new bicyclic pyrazole-based cytokine synthesis inhibitors
Townes, Jennifer A.,Golebiowski, Adam,Clark, Michael P.,Laufersweiler, Matthew J.,Brugel, Todd A.,Sabat, Mark,Bookland, Roger G.,Laughlin, Steve K.,VanRens, John C.,De, Biswanath,Hsieh, Lily C.,Xu, Susan C.,Janusz, Michael J.,Walter, Richard L.
, p. 4945 - 4948 (2007/10/03)
4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-α production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-α production in a THP-1 cell-based assay and against human p38α MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented. 4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-α production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-α production in a THP-1 cell-based assay and against human p38α MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.
Isoxazolone compounds useful in treating diseases associated with unwanted cytokine activity
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, (2008/06/13)
Isoxazolone compounds having the generic structure: are used to treat disease associated with unwanted cytokine activity, including rheumatoid arthritis, osteoarthritis, diabetes, HIV/AIDS, inflammatory bowel disease, Crohn's disease, ulcerative colitis,
3-Heteroaryl-2-pyridones: Benzodiazepine site ligands with functional selectivity for α2/α3-subtypes of human GABAa receptor-ion channels
Collins, Ian,Wafford, Keith,Dawson, Gerard R.,Moyes, Christopher,Davey, William B.,Rowley, Michael,Bromidge, Frances A.,Quirk, Kathleen,Atack, John R.,McKernan, Ruth M.,Thompson, Sally-Ann,Pike, Andrew,Sohal, Bindi,Tsou, Nancy N.,Ball, Richard G.,Castro, José L.
, p. 1887 - 1900 (2007/10/03)
A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human γ-aminobutyric acid (GABAA) receptor ion channels, low binding selectivity for α2- and/or α3- over α1-containing GABAA receptor subtypes and high binding selectivity over α5 subtypes. High affinity appeared to be associated with a coplanar conformation of the pyridone and sulfur-containing 3-heteroaryl rings resulting from an attractive S...O intramolecular interaction. Functional selectivity (i.e., selective efficacy) for α2 and/or α3 GABAA receptor subtypes over α1 was observed in several of these compounds in electrophysiological assays. Furthermore, an α3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an α2/α3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.
