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Novel ferroptosis inhibitors with improved potency and ADME properties

(2016) JOURNAL OF MEDICINAL CHEMISTRY. 59(5). p.2041-2053
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Project
Methusalem program
Abstract
Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia reperfusion injury in mice. A chemical inhibitor discovered by high throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.
Keywords
GPX4, CELL-DEATH

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Citation

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Chicago
Hofmans, Sam, Tom Vanden Berghe, Lars Devisscher, Behrouz Hassannia, Sophie Lyssens, Jurgen Joossens, Pieter Van Der Veken, Peter Vandenabeele, and Koen Augustyns. 2016. “Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties.” Journal of Medicinal Chemistry 59 (5): 2041–2053.
APA
Hofmans, S., Vanden Berghe, T., Devisscher, L., Hassannia, B., Lyssens, S., Joossens, J., Van Der Veken, P., et al. (2016). Novel ferroptosis inhibitors with improved potency and ADME properties. JOURNAL OF MEDICINAL CHEMISTRY, 59(5), 2041–2053.
Vancouver
1.
Hofmans S, Vanden Berghe T, Devisscher L, Hassannia B, Lyssens S, Joossens J, et al. Novel ferroptosis inhibitors with improved potency and ADME properties. JOURNAL OF MEDICINAL CHEMISTRY. 2016;59(5):2041–53.
MLA
Hofmans, Sam, Tom Vanden Berghe, Lars Devisscher, et al. “Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties.” JOURNAL OF MEDICINAL CHEMISTRY 59.5 (2016): 2041–2053. Print.
@article{7176063,
  abstract     = {Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia reperfusion injury in mice. A chemical inhibitor discovered by high throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.},
  author       = {Hofmans, Sam and Vanden Berghe, Tom and Devisscher, Lars and Hassannia, Behrouz and Lyssens, Sophie and Joossens, Jurgen and Van Der Veken, Pieter and Vandenabeele, Peter and Augustyns, Koen},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  language     = {eng},
  number       = {5},
  pages        = {2041--2053},
  title        = {Novel ferroptosis inhibitors with improved potency and ADME properties},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.5b01641},
  volume       = {59},
  year         = {2016},
}

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