1. Structure-activity relationship study of novel necroptosis inhibitors.
- Author
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Teng X, Degterev A, Jagtap P, Xing X, Choi S, Denu R, Yuan J, and Cuny GD
- Subjects
- Animals, Cell Death drug effects, Humans, Hydantoins administration & dosage, Hydantoins chemical synthesis, Injections, Intravenous, Jurkat Cells, Male, Methylation, Mice, Molecular Structure, Necrosis, Structure-Activity Relationship, Tumor Necrosis Factor-alpha pharmacology, Hydantoins chemistry, Hydantoins pharmacology, Sulfhydryl Compounds chemistry
- 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.
- Published
- 2005
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