title: Saccharin derivatives as inhibitors of interferon-mediated inflammation.
abstract: A series of novel, saccharin-based antagonists have been identified for the interferon signaling pathway. Through in vitro high-throughput screening with the Colorado Center for Drug Discovery (C2D2) Pilot Library, we identified hit compound 1, which was the basis for extensive structure-activity relationship studies. Our efforts produced a lead anti-inflammatory compound, tert-butyl N-(furan-2-ylmethyl)-N-{4-[(1,1,3-trioxo-2,3-dihydro-1λ(6),2-benzothiazol-2-yl)methyl]benzoyl}carbamate CU-CPD103 (103), as a potent inhibitor using an established nitric oxide (NO) signaling assay. With further studies of its inhibitory mechanisms, we demonstrated that 103 carries out this inhibition through the JAK/STAT1 pathway, providing a drug-like small molecule inflammation suppressant for possible therapeutic uses.
authors.affiliation: Department of Chemistry & Biochemistry and the BioFrontiers Institute, University of Colorado Boulder , 596 UCB, Boulder, Colorado 80309-0596, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Csakai
authors.forename: Christina
authors.initials: C
authors.lastname: Smith
authors.forename: Emily
authors.initials: E
authors.lastname: Davis
authors.forename: Alexander
authors.initials: A
authors.lastname: Martinko
authors.forename: Sara
authors.initials: S
authors.lastname: Coulup
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D062126:Databases, Chemical; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007372:Interferons / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012439:Saccharin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C000591353:tert-butyl N-(furan-2-ylmethyl)-N-(4-((1,1,3-trioxo-2,3-dihydro-1gamma6,2-benzothiazol-2-yl)methyl)benzoyl)carbamate; D007372:Interferons; D052247:Nitric Oxide Synthase Type II; D053612:Janus Kinases; D012439:Saccharin