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

Tijdschriftbijdrage - Tijdschriftartikel

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.
Tijdschrift: Journal of medicinal chemistry
ISSN: 0022-2623
Volume: 61
Pagina's: 10126 - 10140
Jaar van publicatie:2018
Trefwoorden:A1 Journal article
BOF-keylabel:ja
BOF-publication weight:10
CSS-citation score:2
Authors from:Government
Toegankelijkheid:Open