Structure–activity relationship study of novel necroptosis inhibitors

doi:10.1016/j.bmcl.2005.07.077

Bioorganic & Medicinal Chemistry Letters

Volume 15, Issue 22, 15 November 2005, Pages 5039-5044

https://doi.org/10.1016/j.bmcl.2005.07.077 Get rights and content

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-α. 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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Acknowledgments

X.T., X.X., S.C., P.J., R.D., and G.D.C. thank the Harvard Center for Neurodegeneration and Repair (HCNR) for financial support. A.D. and J.Y. thank the National Institute on Aging, National Institute of General Medical Sciences, and American Health Assistance Foundation for financial support. We thank Dr. Michael Furlong (absorption systems) for insightful discussions about the pharmacokinetic studies. We thank Amano Enzyme Inc. for a supply of D-aminoacylase.

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Structure–activity relationship study of novel necroptosis inhibitors

Abstract

Graphical abstract

Section snippets

Acknowledgments

Int. Rev. Cytol.

Nat. Chem. Biol.

J. Am. Chem. Soc.

Tetrahedron Lett.

Nature

Genes Develop.

J. Med. Chem.

Br. J. Pharmacol.

Oncogene

Brain Res. Bull.

Int. Rev. Cytol.

Nat. Rev. Neurosci.

Am. J. Physiol. Heart Circ. Physiol.

Neuron

Cell Death Differ.

Oncogene

Cell Death Differ.

Curr. Opin. Cell Biol.

Nat. Rev. Mol. Cell Biol.

Clin. Cancer Res.

Infect. Immun.

J. Org. Chem.