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