Development and in vitro profiling of dual FXR/LTA4H modulators

  • 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.
Author:Simone Schierle, Steffen Brunst, Moritz Helmstädter, Roland Ebert, Jan S. Kramer, Dieter SteinhilberORCiDGND, Ewgenij ProschakORCiDGND, Daniel MerkORCiDGND
Parent Title (English):ChemMedChem
Place of publication:Weinheim [u.a.]
Document Type:Article
Date of Publication (online):2021/04/15
Date of first Publication:2021/04/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/04/05
Tag:farnesoid X receptor; leukotriene A4 hydrolase; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; polypharmacology
Page Number:9
First Page:2366
Last Page:2374
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0