Bioorganic & Medicinal Chemistry Letters 2005-11-15

Structure-activity relationship study of novel necroptosis inhibitors.

Xin Teng, Alexei Degterev, Prakash Jagtap, Xuechao Xing, Sungwoon Choi, Régine Denu, Junying Yuan, Gregory D Cuny

Index: Bioorg. Med. Chem. Lett. 15 , 5039, (2005)

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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.