Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
J Med Chem. 2020 Sep 10;63(17):9856-9875. doi: 10.1021/acs.jmedchem.0c01020. Epub 2020 Aug 28.
G-protein-coupled receptor SUCNR1 (succinate receptor 1 or GPR91) senses the citric cycle intermediate succinate and is implicated in various pathological conditions such as rheumatoid arthritis, liver fibrosis, or obesity. Here, we describe a novel SUCNR1 antagonist scaffold discovered by high-throughput screening. The poor permeation and absorption properties of the most potent compounds, which were zwitterionic in nature, could be improved by the formation of an internal salt bridge, which helped in shielding the two opposite charges and thus also the high polarity of zwitterions with separated charges. The designed compounds containing such a salt bridge reached high oral bioavailability and oral exposure. We believe that this principle could find a broad interest in the medicinal chemistry field as it can be useful not only for the modulation of properties in zwitterionic compounds but also in acidic or basic compounds with poor permeation.
G 蛋白偶联受体 SUCNR1（琥珀酸受体 1 或 GPR91）感知柠檬酸循环中间体琥珀酸，并与各种病理状况有关，如类风湿性关节炎、肝纤维化或肥胖症。在这里，我们描述了一种通过高通量筛选发现的新型 SUCNR1 拮抗剂支架。由于大多数具有两性离子性质的化合物具有较差的渗透和吸收性能，因此通过形成内部盐桥可以改善其性能，这有助于屏蔽两个相反的电荷，从而也可以屏蔽具有分离电荷的两性离子的高极性。设计的含有这种盐桥的化合物具有较高的口服生物利用度和口服暴露量。我们相信，这个原理在药物化学领域可能会引起广泛的兴趣，因为它不仅可以用于调节两性离子化合物的性质，而且可以用于改善具有较差渗透性的酸性或碱性化合物。
