E-viri
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Neukirch, Konstantin; Alsabil, Khaled; Dinh, Chau-Phi; Bilancia, Rossella; Raasch, Martin; Ville, Alexia; Cerqua, Ida; Viault, Guillaume; Bréard, Dimitri; Pace, Simona; Temml, Veronika; Brunner, Elena; Jordan, Paul M; Marques, Marta C; Loeser, Konstantin; Gollowitzer, André; Permann, Stephan; Gerstmeier, Jana; Lorkowski, Stefan; Stuppner, Hermann; Garscha, Ulrike; Rodrigues, Tiago; Bernardes, Gonçalo J. L; Schuster, Daniela; Séraphin, Denis; Richomme, Pascal; Rossi, Antonietta; Mosig, Alexander S; Roviezzo, Fiorentina; Werz, Oliver; Helesbeux, Jean-Jacques; Koeberle, Andreas
Journal of medicinal chemistry, 08/2021, Letnik: 64, Številka: 15Journal Article
Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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