Title
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Discovery of novel, drug-like ferroptosis inhibitors with in vivo efficacy
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Author
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Abstract
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Ferroptosis is an iron-catalysed, non-apoptotic 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 multi-organ 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. Concludingly, 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. |
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Language
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English
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Source (journal)
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Journal of medicinal chemistry. - Washington, D.C., 1963, currens
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Publication
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Washington, D.C.
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2018
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ISSN
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0022-2623
[print]
1520-4804
[online]
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DOI
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10.1021/ACS.JMEDCHEM.8B01299
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Volume/pages
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61
:22
(2018)
, p. 10126-10140
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ISI
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000451496300019
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Pubmed ID
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30354101
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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