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 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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Author:Simone SchierleGND, Moritz HelmstädterORCiDGND, Jurema SchmidtGND, Markus Hartmann, Maximiliane Horz, Astrid Kaiser, Lilia Weizel, Pascal HeitelORCiDGND, Anna Proschak, Victor Hernandez‐OlmosORCiD, Ewgenij ProschakORCiDGND, Daniel MerkORCiDGND
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/31670489
Parent Title (German):ChemMedChem
Place of publication:Weinheim
Document Type:Article
Date of Publication (online):2019/10/31
Date of first Publication:2019/10/31
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/12/10
Tag:NAFLD; NASH; Polypharmacology; non-alcoholic steatohepatitis; nuclear receptor
Page Number:18
First Page:50
Last Page:67
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (English):License LogoCreative Commons - Namensnennung-Nicht kommerziell 4.0