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Discovery of novel, drug-like ferroptosis inhibitors with in vivo efficacy

(2018) JOURNAL OF MEDICINAL CHEMISTRY. 61(22). p.10126-10140
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Abstract
Ferroptosis is an iron-catalyzed, nonapoptotic form of regulated necrosis that results in oxidative lipid damage in cell membranes that can be inhibited by the radical-trapping antioxidant Ferrostatin-1 (Fer-1). Novel inhibitors derived from the Fer-1 scaffold inhibited ferroptosis potently but suffered from solubility issues. In this paper, we report the synthesis of a more stable and readily soluble series of Fer-1 analogues that potently inhibit ferroptosis. The most promising compounds (37, 38, and 39) showed an improved protection compared to Fer-1 against multiorgan injury in mice. No toxicity was observed in mice after daily injection of 39 (UAMC-3203) for 4 weeks. UAMC-3203 inserts rapidly in a phospholipid bilayer in silico, which aligns with the current understanding of the mechanism of action of these compounds. In conclusion, these analogues have superior properties compared to Fer-1, show in vivo efficacy, and represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models.
Keywords
GLUTATHIONE-PEROXIDASE 4, CELL-DEATH, MOLECULAR-DYNAMICS, LIPID-PEROXIDATION, IRON, MECHANISMS, VALIDATION

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Chicago
Devisscher, Lars, Samya Van Coillie, Sam Hofmans, Dries Van Rompaey, Kenneth Goossens, Eline Meul, Louis Maes, et al. 2018. “Discovery of Novel, Drug-like Ferroptosis Inhibitors with in Vivo Efficacy.” Journal of Medicinal Chemistry 61 (22): 10126–10140.
APA
Devisscher, Lars, Van Coillie, S., Hofmans, S., Van Rompaey, D., Goossens, K., Meul, E., Maes, L., et al. (2018). Discovery of novel, drug-like ferroptosis inhibitors with in vivo efficacy. JOURNAL OF MEDICINAL CHEMISTRY, 61(22), 10126–10140.
Vancouver
1.
Devisscher L, Van Coillie S, Hofmans S, Van Rompaey D, Goossens K, Meul E, et al. Discovery of novel, drug-like ferroptosis inhibitors with in vivo efficacy. JOURNAL OF MEDICINAL CHEMISTRY. 2018;61(22):10126–40.
MLA
Devisscher, Lars et al. “Discovery of Novel, Drug-like Ferroptosis Inhibitors with in Vivo Efficacy.” JOURNAL OF MEDICINAL CHEMISTRY 61.22 (2018): 10126–10140. Print.
@article{8600958,
  abstract     = {Ferroptosis is an iron-catalyzed, nonapoptotic form of regulated necrosis that results in oxidative lipid damage in cell membranes that can be inhibited by the radical-trapping antioxidant Ferrostatin-1 (Fer-1). Novel inhibitors derived from the Fer-1 scaffold inhibited ferroptosis potently but suffered from solubility issues. In this paper, we report the synthesis of a more stable and readily soluble series of Fer-1 analogues that potently inhibit ferroptosis. The most promising compounds (37, 38, and 39) showed an improved protection compared to Fer-1 against multiorgan injury in mice. No toxicity was observed in mice after daily injection of 39 (UAMC-3203) for 4 weeks. UAMC-3203 inserts rapidly in a phospholipid bilayer in silico, which aligns with the current understanding of the mechanism of action of these compounds. In conclusion, these analogues have superior properties compared to Fer-1, show in vivo efficacy, and represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models.},
  author       = {Devisscher, Lars and Van Coillie, Samya and Hofmans, Sam and Van Rompaey, Dries and Goossens, Kenneth and Meul, Eline and Maes, Louis and De Winter, Hans and Van Der Veken, Pieter and Vandenabeele, Peter and Vanden Berghe, Tom and Augustyns, Koen},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  language     = {eng},
  number       = {22},
  pages        = {10126--10140},
  title        = {Discovery of novel, drug-like ferroptosis inhibitors with in vivo efficacy},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.8b01299},
  volume       = {61},
  year         = {2018},
}

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