title: Structure-activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors.
abstract: Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling non-regulated necrosis. This form of cell death can be induced in an array of cell types in apoptotic deficient conditions with death receptor family ligands. A series of [1,2,3]thiadiazole benzylamides was found to be potent necroptosis inhibitors (called necrostatins). A structure-activity relationship study revealed that small cyclic alkyl groups (i.e. cyclopropyl) and 2,6-dihalobenzylamides at the 4- and 5-positions of the [1,2,3]thiadiazole, respectively, were optimal. In addition, when a small alkyl group (i.e. methyl) was present on the benzylic position all the necroptosis inhibitory activity resided with the (S)-enantiomer. Finally, replacement of the [1,2,3]thiadiazole with a variety of thiophene derivatives was tolerated, although some erosion of potency was observed.
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair, 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: Arumugasamy
authors.initials: A
authors.lastname: Jeevanandam
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D015394:Molecular Structure; D009336:Necrosis / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D013830:Thiadiazoles; D014409:Tumor Necrosis Factor-alpha