Design and structural optimization of dual FXR/PPARδ activators
Abstract
Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δ have been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPARδ-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδ activator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδ and was structurally refined to a potent and balanced FXR/PPARδ activator in a computer-aided fashion. The resulting dual FXR/PPARδ modulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings.
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Dual FXR/PPARδ agonists are currently developed for treatment of NASH.
“Interestingly, in extension of dual PPARα/γ and α/δ agonists, dual FXR/PPARδ agonists are currently developed for treatment of NASH.235”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [235]
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Novel therapeutic targets for cholestatic and fatty liver disease
Trauner, M., & Fuchs, C. D. (2022) · Gut · doi:10.1136/gutjnl-2021-324305 · Cited by 204 · see citing works
- Authors
- Schierle, S., Neumann, S., Heitel, P., Willems, S., Kaiser, A., Pollinger, J., & Merk, D.
- Affiliations
- Goethe University Frankfurt (DE)
- Corresponding author
- Merk, Daniel
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-07-20
- Volume
- 63
- Issue
- 15
- Pages
- 8369-8379
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W3043067184
- Cited by
- 34
- References
- 23
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 4 · 2023: 8 · 2022: 4 · 2021: 6
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Aventis Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- farnesoid X receptor, PPARδ, nonalcoholic steatohepatitis, nuclear receptor agonists, multi-target drug design, structure-activity optimization, computer-aided drug design, metabolic syndrome
- MeSH terms
- Receptor, Farnesoid X-Activated, Humans, Ligands, Structure-Activity Relationship, Drug Design, Receptors, Cytoplasmic and Nuclear, PPAR delta, Drug Discovery, Molecular Docking Simulation, Non-alcoholic Fatty Liver Disease
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