A New FXR Ligand Chemotype with Agonist/Antagonist Switch
Moritz Helmstädter1, Jan Vietor1, Jana Sommer1
1Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
ACS Medicinal Chemistry Letters
|February 19, 2021
Summary
Researchers developed novel farnesoid X receptor (FXR) modulators with tunable activity. This new scaffold offers potential for treating liver and metabolic diseases by expanding FXR-targeted drug discovery options.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Hepatology
Background:
- Farnesoid X receptor (FXR) is a key target for treating hepatic and metabolic diseases.
- Existing FXR modulators lack structural diversity, necessitating new ligand scaffolds.
Purpose of the Study:
- To elucidate structure-activity relationships of a novel FXR modulator chemotype.
- To develop selective FXR agonists and antagonists with tunable activity.
Main Methods:
- Structure-activity relationship (SAR) studies of a new chemical series.
- Development of selective FXR activators and antagonists.
- Assessment of cellular activity, metabolic stability, and cytotoxicity.
Main Results:
- Identified a new FXR modulator chemotype with tunable agonism/antagonism via minor structural modifications.
- Achieved nanomolar to low-micromolar potencies and binding affinities for selective FXR modulators.
- Demonstrated modulation of FXR activity in a cellular context, with favorable metabolic stability and no cytotoxicity.
Conclusions:
- A novel FXR ligand scaffold has been developed, expanding the repertoire of FXR modulators.
- This new chemotype provides a valuable platform for FXR-targeted drug discovery.
- The tunable nature of these modulators offers flexibility for therapeutic applications in liver and metabolic diseases.
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