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.
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| Author: | Simone SchierleGND, Steffen Brunst, Moritz HelmstädterORCiDGND, Roland Ebert, Jan S. Kramer, Dieter SteinhilberORCiDGND, Ewgenij ProschakORCiDGND, Daniel MerkORCiDGND |
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| URN: | urn:nbn:de:hebis:30:3-638861 |
| DOI: | https://doi.org/10.1002/cmdc.202100118 |
| ISSN: | 1860-7187 |
| Parent Title (English): | ChemMedChem |
| Publisher: | Wiley-VCH |
| Place of publication: | Weinheim [u.a.] |
| Document Type: | Article |
| Language: | English |
| 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 |
| Volume: | 16 |
| Issue: | 15 |
| Page Number: | 9 |
| First Page: | 2366 |
| Last Page: | 2374 |
| HeBIS-PPN: | 493480277 |
| 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 | |
| Sammlungen: | Universitätspublikationen |
| Licence (German): |  Creative Commons - Namensnennung 4.0 |
