Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.
Bioorg Med Chem. 2012 Oct 1;20(19):5864-83. doi: 10.1016/j.bmc.2012.07.046. Epub 2012 Aug 5.
In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8-positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7-position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7-carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction.
近年来，二肽基肽酶 IV 抑制剂已被认为是治疗 2 型糖尿病的有价值药物。在此，我们报告了一种新型强效 DPP-4 抑制剂的发现，其骨架为 3H-咪唑并[4,5-c]喹啉-4(5H)-酮。在使用对接研究对先导化合物 2a 在 7-和 8-位进行有效优化后，我们发现 28 是一种新型 DPP-4 抑制剂，对各种 DPP-4 同源物具有优异的选择性。与市售的 DPP-4 抑制剂相比，化合物 28 显示出较强的 DPP-4 抑制活性。我们还发现 7-位的羧基可以与残基 Lys554 相互作用形成盐桥。此外，在 7-位引入羧基可同时增强活性并降低 hERG 通道抑制和诱导磷脂化的风险。在我们合成具有 7-羧基的化合物时，我们在分子内钯偶联反应中使用大体积酯实现了高效的区域选择性合成。
