TY  - JOUR
A1  - Heitel, Pascal
A1  - Faudone, Giuseppe
A1  - Helmstädter, Moritz
A1  - Schmidt, Jurema
A1  - Kaiser, Astrid
A1  - Tjaden, Amelie
A1  - Schröder, Martin
A1  - Müller, Susanne
A1  - Schierle, Simone
A1  - Pollinger, Julius Carl
A1  - Merk, Daniel
T1  - A triple farnesoid X receptor and peroxisome proliferator-activated receptor α/δ activator reverses hepatic fibrosis in diet-induced NASH in mice
T2  - Communications chemistry
N2  - Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.
KW  - Medicinal chemistry
KW  - Pharmacology
KW  - Small molecules
KW  - Target validation
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/75068
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-750681
SN  - 2399-3669
N1  - This research was financially supported by the WIPANO program of the German Federal Ministry for Economic Affairs and Energy (grant 03THW10H09) and by the Aventis Foundation.
Open Access funding enabled and organized by Projekt DEAL.
VL  - 3
IS  - art. 174
SP  - 1
EP  - 16
PB  - Macmillan Publishers Limited, part of Springer Nature
CY  - [London]
ER  -