US EPA

7098343 

Journal Article 

Discovery of Novel, Drug-Like Ferroptosis Inhibitors with in Vivo Efficacy 

Devisscher, L; Vandenabeele, P; Vanden Berghe, Tom; Augustyns, K; Van Coillie, S; Hofmans, Sam; Van Rompaey, D; Goossens, K; Meul, E; Maes, L; De Winter, H; Van Der Veken, P; , 

2018 

Yes 

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 

AMER CHEMICAL SOC 

WASHINGTON 

61 

22 

10126-10140 

English 

30354101 

10.1021/acs.jmedchem.8b01299 

WOS:000451496300019 

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. 

3 (benzylamino) 4 (cyclohexylamino) n (2 methoxyethyl)benzenesulfonamide; 3 (benzylamino) 4 (cyclohexylamino) n (2 morpholinoethyl)benzenesulfonamide; 3 (benzylamino) 4 (cyclohexylamino) n [2 (4 methylpiperazin 1 yl)ethyl]benzenesulfonamide; 3 (benzylamino) 4 (cyclohexylamino) n [2 (dimethylamino)ethyl]benzenesulfonamide; 3 (benzylamino) 4 (cyclohexylamino) n [2 (methylamino)ethyl]benzenesulfonamide; 3 (benzylamino) 4 (cyclohexylamino) n [2 (piperazin 1 yl)ethyl]benzenesulfonamide; 3 amino 4 (cyclohexylamino) n (2 methoxyethyl)benzenesulfonamide; 3 amino 4 (cyclohexylamino) n (2 morpholinoethyl)benzenesulfonamide; 3 amino 4 (cyclohexylamino) n [2 (4 methylpiperazin 1 yl)ethyl]benzenesulfonamide; 3 amino 4 (cyclohexylamino) n [2 (dimethylamino)ethyl]benzenesulfonamide; 3 amino 4 (cyclohexylamino) n [2 (methylamino)ethyl]benzenesulfonamide; 3 amino 4 (cyclohexylamino) n [2 (piperazin 1 yl)ethyl]benzenesulfonamide; 3 amino n (2 aminoethyl) 4 (cyclohexylamino)benzenesulfonamide; 4 (cyclohexylamino) n (2 methoxyethyl) 3 [(pyridin 4 ylmethyl)amino]benzenesulfonamide; 4 (cyclohexylamino) n (2 morpholinoethyl) 3 [(pyridin 4 ylmethyl)amino]benzenesulfonamide; 4 (cyclohexylamino) n [2 (dimethylamino)ethyl] 3 [(pyridin 4 ylmethyl)amino]benzenesulfonamide; antioxidant; apoptosis inhibitor; ferrostatin 1; n (2 aminoethyl) 3 (benzylamino) 4 (cyclohexylamino)benzenesulfonamide; tert butyl 4 [2 [[3 (benzylamino) 4 (cyclohexylamino)phenyl]sulfonamido]ethyl)piperazine 1 carboxylate; tert butyl 4 [2 [[3 amino 4 (cyclohexylamino)phenyl]sulfonamido]ethyl]piperazine 1 carboxylate; tert butyl 4 [2 [[4 (cyclohexylamino) 3 [(pyridin 4 ylmethyl)amino]phenyl]sulfonamido]ethyl]piperazine 1 carboxylate; tert butyl [2 [[3 (benzylamino) 4 (cyclohexylamino)phenyl]sulfonamido]ethyl](methyl)carbamate; tert butyl [2 [[3 (benzylamino) 4 (cyclohexylamino)phenyl]sulfonamido]ethyl]carbamate; tert butyl [2 [[3 amino 4 (cyclohexylamino)phenyl]sulfonamido]ethyl](methyl)carbamate; tert butyl [2 [[3 amino 4 (cyclohexylamino)phenyl]sulfonamido]ethyl]carbamate; tert butyl [2 [[4 (cyclohexylamino) 3 [(pyridin 4 ylmethyl)amino]phenyl]sulfonamido]ethyl](methyl)carbamate; tert butyl [2 [[4 (cyclohexylamino) 3 [(pyridin 4 ylmethyl)amino]phenyl]sulfonamido]ethyl]carbamate; uamc 3203; uamc 3206; uamc 3234; unclassified drug; unindexed drug; cyclohexylamine derivative; ferrostatin-1; phenylenediamine derivative; animal experiment; animal model; Article; binding affinity; computer model; controlled study; drug absorption; drug blood level; drug distribution; drug efficacy; drug excretion; drug half life; drug mechanism; drug metabolism; drug solubility; drug synthesis; ferroptosis; human; human cell; IC50; IMR-32 cell line; in vitro study; in vivo study; intrinsic clearance; metabolic stability; molecular dynamics; mouse; multiple organ failure; nonhuman; phospholipid bilayer; rat; tissue distribution; animal; apoptosis; cell membrane; conformation; drug design; drug effect; metabolism; molecular model; oxidative stress; tumor cell line; Animals; Apoptosis; Cell Line, Tumor; Cell Membrane; Cyclohexylamines; Drug Design; Humans; Mice; Models, Molecular; Molecular Conformation; Oxidative Stress; Phenylenediamines; Rats; Tissue Distribution