Structure-activity relationship study of novel necroptosis inhibitors

  • Bioorg Med Chem Lett. 2005 Nov 15;15(22):5039-44. doi: 10.1016/j.bmcl.2005.07.077.
Xin Teng  1 ,  Alexei Degterev ,  Prakash Jagtap ,  Xuechao Xing ,  Sungwoon Choi ,  Régine Denu ,  Junying Yuan ,  Gregory D Cuny
Affiliations
  • 1. 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.
PMID: 16153840 DOI: 10.1016/j.bmcl.2005.07.077
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.

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