title: Structure-activity relationship study of novel necroptosis inhibitors.
abstract: Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling necrosis. It can be induced in a FADD-deficient variant of human Jurkat T cells treated with TNF-alpha. 5-(1H-Indol-3-ylmethyl)-2-thiohydantoins and 5-(1H-indol-3-ylmethyl)hydantoins were found to be potent necroptosis inhibitors (called necrostatins). A SAR study revealed that several positions of the indole were intolerant of substitution, while small substituents at the 7-position resulted in increased inhibitory activity. The hydantoin ring was also quite sensitive to structural modifications. A representative member of this compound class demonstrated moderate pharmacokinetic characteristics and readily entered the central nervous system upon intravenous administration.
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: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Prakash
authors.initials: P
authors.lastname: Jagtap
authors.forename: Xuechao
authors.initials: X
authors.lastname: Xing
authors.forename: Sungwoon
authors.initials: S
authors.lastname: Choi
authors.forename: Régine
authors.initials: R
authors.lastname: Denu
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D006801:Humans; D006827:Hydantoins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007275:Injections, Intravenous; D019169:Jurkat Cells; D008297:Male; D008745:Methylation; D051379:Mice; D015394:Molecular Structure; D009336:Necrosis; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D006827:Hydantoins; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha