A New FXR Ligand Chemotype with Agonist/Antagonist Switch.

Therapeutic modulation of the bile acid-sensing transcription factor farnesoid X receptor (FXR) is an appealing strategy to counteract hepatic and metabolic diseases. Despite the availability of several highly potent FXR agonists structural diversity of FXR modulators is limited, and new ligand scaffolds are needed. Here we report structure-activity relationship elucidation of a new FXR modulator chemotype whose activity can be tuned between agonism and antagonism by two minor structural modifications. Starting from a weak FXR/PPAR agonist, we have developed selective FXR activators and antagonists with nanomolar to low-micromolar potencies and binding affinities. The new FXR ligand chemotype modulates the FXR activity in the native cellular setting, is endowed with favorable metabolic stability, and lacks cytotoxicity. It valuably expands the collection of FXR modulators as a new scaffold for FXR-targeted drug discovery. © 2021 The Authors. Published by American Chemical Society.

Citation

Moritz Helmstädter, Jan Vietor, Jana Sommer, Simone Schierle, Sabine Willems, Astrid Kaiser, Jurema Schmidt, Daniel Merk. A New FXR Ligand Chemotype with Agonist/Antagonist Switch. ACS medicinal chemistry letters. 2021 Feb 11;12(2):267-274

PMID: 33603974

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