Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast

The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non‐alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti‐NASH effects and thus may generate s...

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Detalles Bibliográficos
Autores principales: Schierle, Simone, Helmstädter, Moritz, Schmidt, Jurema, Hartmann, Markus, Horz, Maximiliane, Kaiser, Astrid, Weizel, Lilia, Heitel, Pascal, Proschak, Anna, Hernandez‐Olmos, Victor, Proschak, Ewgenij, Merk, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Full Papers
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004070/
https://www.ncbi.nlm.nih.gov/pubmed/31670489
http://dx.doi.org/10.1002/cmdc.201900576
Descripción
Sumario:The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non‐alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti‐NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti‐asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver‐related metabolic diseases.

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