Extending the Structure鈥揂ctivity Relationship of Anthranilic Acid Derivatives As Farnesoid X Receptor Modulators: Development of a Highly Potent Partial Farnesoid X Receptor Agonist

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• 作者：Daniel Merk ; Christina Lamers ; Khalil Ahmad ; Roberto Carrasco Gomez ; Gisbert Schneider ; Dieter Steinhilber ; Manfred Schubert-Zsilavecz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：57
• 期：19
• 页码：8035-8055
• 全文大小：986K
• ISSN：1520-4804

文摘

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 卤 3 nM and on mRNA level in liver cells.