Flesch Daniel, Gabler Matthias, Lill Andreas, Gomez Roberto Carrasco, Steri Ramona, Schneider Gisbert, Stark Holger, Schubert-Zsilavecz Manfred, Merk Daniel
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog Weg 1-5/10, 8093 Zürich, Switzerland.
Bioorg Med Chem. 2015 Jul 1;23(13):3490-8. doi: 10.1016/j.bmc.2015.04.035. Epub 2015 Apr 18.
The ligand activated transcription factor farnesoid X receptor (FXR) is a crucial regulator of several metabolic and inflammatory pathways and its activation by agonistic ligands seems a valuable therapeutic approach for many disorders. Most known non-steroidal FXR agonists however, have limitations that hinder their clinical development and novel FXR ligands are required. Evaluation of the co-crystal structures of the widely used FXR agonist GW4064 and related compounds in complex with the FXR ligand binding domain indicated that their disubstituted isoxazole moiety is especially relevant for FXR activation. By investigation of GW4064-fragments missing the aromatic tail, we discovered a highly potent and soluble partial FXR agonist (14, ST-1892) as well as a fluorescent FXR ligand (15) as potential pharmacological tool.
配体激活的转录因子法尼酯X受体（FXR）是多种代谢和炎症途径的关键调节因子，通过激动剂配体激活它似乎是治疗许多疾病的一种有价值的方法。然而，大多数已知的非甾体FXR激动剂都存在限制其临床开发的问题，因此需要新型FXR配体。对广泛使用的FXR激动剂GW4064及相关化合物与FXR配体结合域复合物的共晶体结构评估表明，其二取代异恶唑部分对FXR激活尤为重要。通过研究缺失芳香尾的GW4064片段，我们发现了一种高效且可溶的部分FXR激动剂（14，ST-1892）以及一种荧光FXR配体（15）作为潜在的药理学工具。
