Helmstädter Moritz, Vietor Jan, Sommer Jana, Schierle Simone, Willems Sabine, Kaiser Astrid, Schmidt Jurema, Merk Daniel
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
ACS Med Chem Lett. 2021 Feb 1;12(2):267-274. doi: 10.1021/acsmedchemlett.0c00647. eCollection 2021 Feb 11.
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.
对胆汁酸传感转录因子法尼酯X受体（FXR）进行治疗性调控是对抗肝脏疾病和代谢性疾病的一种有吸引力的策略。尽管已有几种高效的FXR激动剂，但FXR调节剂的结构多样性有限，因此需要新的配体支架。在此，我们报告了一种新型FXR调节剂化学类型的构效关系解析，其活性可通过两个微小的结构修饰在激动作用和拮抗作用之间进行调节。从一种弱FXR/PPAR激动剂开始，我们开发了具有纳摩尔至低微摩尔效力和结合亲和力的选择性FXR激活剂和拮抗剂。这种新型FXR配体化学类型在天然细胞环境中调节FXR活性，具有良好的代谢稳定性，且无细胞毒性。它作为FXR靶向药物发现的新支架，极大地扩展了FXR调节剂的种类。
