TY  - JOUR
A1  - Schierle, Simone
A1  - Helmstädter, Moritz
A1  - Schmidt, Jurema
A1  - Hartmann, Markus
A1  - Horz, Maximiliane
A1  - Kaiser, Astrid
A1  - Weizel, Lilia
A1  - Heitel, Pascal
A1  - Proschak, Anna
A1  - Hernandez‐Olmos, Victor
A1  - Proschak, Ewgenij
A1  - Merk, Daniel
T1  - Dual farnesoid X receptor/soluble epoxide hydrolase modulators derived from Zafirlukast
T2  - ChemMedChem
N2  - 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.
KW  - Polypharmacology
KW  - non-alcoholic steatohepatitis
KW  - NASH
KW  - NAFLD
KW  - nuclear receptor
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/57041
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-570413
SN  - 1860-7187
VL  - 15.2020
IS  - 1
SP  - 50
EP  - 67
PB  - Wiley-VCH
CY  - Weinheim
ER  -