Exploration of Long-Chain Vitamin e Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

Neukirch, K.; Alsabil, K.; Dinh, C. -P.; Bilancia, R.; Raasch, M.; Ville, A.; Cerqua, I.; Viault, G.; Breard, D.; Pace, S.; Temml, V.; Brunner, E.; Jordan, P. M.; Marques, M. C.; Loeser, K.; Gollowitzer, A.; Permann, S.; Gerstmeier, J.; Lorkowski, S.; Stuppner, H.; Garscha, U.; Rodrigues, T.; Bernardes, G. J. L.; Schuster, D.; Seraphin, D.; Richomme, P.; Rossi, A.; Mosig, A. S.; Roviezzo, F.; Werz, O.; Helesbeux, J. -J.; Koeberle, A.

doi:10.1021/acs.jmedchem.1c00806

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.

Exploration of Long-Chain Vitamin e Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation / Neukirch, K.; Alsabil, K.; Dinh, C. -P.; Bilancia, R.; Raasch, M.; Ville, A.; Cerqua, I.; Viault, G.; Breard, D.; Pace, S.; Temml, V.; Brunner, E.; Jordan, P. M.; Marques, M. C.; Loeser, K.; Gollowitzer, A.; Permann, S.; Gerstmeier, J.; Lorkowski, S.; Stuppner, H.; Garscha, U.; Rodrigues, T.; Bernardes, G. J. L.; Schuster, D.; Seraphin, D.; Richomme, P.; Rossi, A.; Mosig, A. S.; Roviezzo, F.; Werz, O.; Helesbeux, J. -J.; Koeberle, A.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:15(2021), pp. 11496-11526. [10.1021/acs.jmedchem.1c00806]