TY  - JOUR
A1  - Schierle, Simone
A1  - Brunst, Steffen
A1  - Helmstädter, Moritz
A1  - Ebert, Roland
A1  - Kramer, Jan S.
A1  - Steinhilber, Dieter
A1  - Proschak, Ewgenij
A1  - Merk, Daniel
T1  - Development and in vitro profiling of dual FXR/LTA4H modulators
T2  - ChemMedChem
N2  - Designed polypharmacology presents as an attractive strategy to increase therapeutic efficacy in multi-factorial diseases by a directed modulation of multiple involved targets with a single molecule. Such an approach appears particularly suitable in non-alcoholic steatohepatitis (NASH) which involves hepatic steatosis, inflammation and fibrosis as pathological hallmarks. Among various potential pharmacodynamic mechanisms, activation of the farnesoid X receptor (FXRa) and inhibition of leukotriene A4 hydrolase (LTA4Hi) hold promise to counteract NASH according to preclinical and clinical observations. We have developed dual FXR/LTA4H modulators as pharmacological tools, enabling evaluation of this polypharmacology concept to treat NASH and related pathologies. The optimized FXRa/LTA4Hi exhibits well-balanced dual activity on the intended targets with sub-micromolar potency and is highly selective over related nuclear receptors and enzymes rendering it suitable as tool to probe synergies of dual FXR/LTA4H targeting.
KW  - farnesoid X receptor
KW  - leukotriene A4 hydrolase
KW  - polypharmacology
KW  - non-alcoholic steatohepatitis
KW  - non-alcoholic fatty liver disease
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63886
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-638861
SN  - 1860-7187
VL  - 16
IS  - 15
SP  - 2366
EP  - 2374
PB  - Wiley-VCH
CY  - Weinheim [u.a.]
ER  -