Merk Daniel, Lamers Christina, Weber Julia, Flesch Daniel, Gabler Matthias, Proschak Ewgenij, Schubert-Zsilavecz Manfred
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
Bioorg Med Chem. 2015 Feb 1;23(3):499-514. doi: 10.1016/j.bmc.2014.12.013. Epub 2014 Dec 19.
Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of anthranilic acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism.
核受体，尤其是过氧化物酶体增殖物激活受体（PPARs）和法尼酯X受体（FXR）在代谢平衡中发挥着关键作用。它们的激活具有重要的治疗潜力，这与作为PPAR激动剂药物的贝特类药物和格列酮类药物具有高度临床相关性。随着对核受体在许多疾病中各种功能的了解不断增加，然而仍需要这些药物靶点的新型选择性或双重配体。在此我们报道邻氨基苯甲酸衍生物类作为新型选择性PPAR或双重FXR/PPAR配体。我们确定了决定对每种PPAR亚型或FXR选择性以及各自受体激活幅度的不同分子决定因素。由此我们发现了几种用于进一步优化的先导化合物，并开发了一种高效的双重PPARα/FXR部分激动剂，通过同时激活参与脂质代谢的两种核受体，可能对脂质稳态产生有益的协同作用。
