Merk Daniel, Lamers Christina, Ahmad Khalil, Carrasco Gomez Roberto, Schneider Gisbert, Steinhilber Dieter, Schubert-Zsilavecz Manfred
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt , Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
J Med Chem. 2014 Oct 9;57(19):8035-55. doi: 10.1021/jm500937v. Epub 2014 Sep 25.
The ligand activated transcription factor nuclear farnesoid X receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the receptor to the full extent which might be disadvantageous over a longer time period. Hence, partial FXR activators are required for long-term treatment of metabolic disorders. We here report the SAR of anthranilic acid derivatives as FXR modulators and development, synthesis, and characterization of compound 51, which is a highly potent partial FXR agonist in a reporter gene assay with an EC50 value of 8 ± 3 nM and on mRNA level in liver cells.
配体激活的转录因子核法尼醇X受体（FXR）作为一种调节因子参与许多代谢途径，包括胆汁酸和葡萄糖稳态。因此，FXR的药理学激活似乎是治疗多种疾病的一种有价值的治疗方法，这些疾病包括与胰岛素抵抗相关的代谢性疾病、原发性胆汁性肝硬化或非酒精性脂肪性肝炎等肝脏疾病以及某些形式的癌症。然而，现有的FXR激动剂会使受体完全激活，这在较长时间内可能是不利的。因此，需要部分FXR激活剂来长期治疗代谢紊乱。我们在此报告邻氨基苯甲酸衍生物作为FXR调节剂的构效关系以及化合物51的开发、合成和表征，该化合物在报告基因测定中是一种高效的部分FXR激动剂，EC50值为8±3 nM，在肝细胞的mRNA水平上也有此效果。
