四氢喹啉酮游离脂肪酸受体 3 调节剂的构效关系研究。
Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators.
机构信息
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
出版信息
J Med Chem. 2020 Apr 9;63(7):3577-3595. doi: 10.1021/acs.jmedchem.9b02036. Epub 2020 Mar 19.
Free fatty acid receptor 3 (FFA3, previously GPR41) is activated by short-chain fatty acids, mediates health effects of the gut microbiota, and is a therapeutic target for metabolic and inflammatory diseases. The shortage of well-characterized tool compounds has however impeded progress. Herein, we report structure-activity relationship of an allosteric modulator series and characterization of physicochemical and pharmacokinetic properties of selected compounds, including previous and new tools. Two representatives, (TUG-1907) and (TUG-2015), showed improved solubility and preserved potency. Of these, , with EC = 145 nM and a solubility of 33 μM, showed high clearance in vivo but is a preferred tool in vitro. In contrast, , with EC = 162 nM and a solubility of 9 μM, showed lower clearance and seems better suited for in vivo studies. Using , we demonstrate for the first time that FFA3 activation leads to calcium mobilization in murine dorsal root ganglia.
游离脂肪酸受体 3（FFA3，以前称为 GPR41）可被短链脂肪酸激活，介导肠道微生物群的健康效应，是代谢和炎症性疾病的治疗靶点。然而，缺乏特征明确的工具化合物阻碍了研究进展。在此，我们报告了一种别构调节剂系列的构效关系，并对选定化合物的理化和药代动力学特性进行了表征，包括以前和新的工具化合物。两种代表性化合物 （TUG-1907）和 （TUG-2015）显示出改善的溶解度和保留的效力。其中，EC = 145 nM 且溶解度为 33 μM 的 ，具有较高的体内清除率，但在体外是一种首选工具化合物。相比之下，EC = 162 nM 且溶解度为 9 μM 的 ，具有较低的清除率，似乎更适合体内研究。使用 ，我们首次证明 FFA3 的激活可导致小鼠背根神经节中的钙动员。
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