title: Structure-activity relationship and liver microsome stability studies of pyrrole necroptosis inhibitors.
abstract: Necroptosis is a regulated caspase-independent cell death pathway resulting in morphology reminiscent of passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of [1,2,3]thiadiazole benzylamide derivatives. However, initial evaluation of mouse liver microsome stability indicated that this series of compounds was rapidly degraded. A structure-activity relationship (SAR) study of the [1,2,3]thiadiazole benzylamide series revealed that increased mouse liver microsome stability and increased necroptosis inhibitory activity could be accomplished by replacement of the 4-cyclopropyl-[1,2,3]thiadiazole with a 5-cyano-1-methylpyrrole. In addition, the SAR and the cellular activity profiles, utilizing different cell types and necroptosis-inducing stimuli, of representative [1,2,3]thiadiazole and pyrrole derivatives were very similar suggesting that the two compound series inhibit necroptosis in the same manner.
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Teng
authors.forename: Heather
authors.initials: H
authors.lastname: Keys
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D009336:Necrosis / Q000188:drug therapy / Q000473:pathology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha