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Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2012-08-04 , DOI: 10.1016/j.bmc.2012.07.046
Yohei Ikuma , Hitoshi Hochigai , Hidenori Kimura , Noriko Nunami , Tomonori Kobayashi , Katsuya Uchiyama , Yudai Furuta , Mutsuko Sakai , Masakuni Horiguchi , Yumi Masui , Kazuhiko Okazaki , Yasuhiro Sato , Hiroyuki Nakahira

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.



中文翻译:

3 H-咪唑并[4,5 - c ]喹啉-4(5 H)-ones作为有效的和选择性的二肽基肽酶IV(DPP-4)抑制剂的发现

近年来,二肽基肽酶IV抑制剂被认为是治疗2型糖尿病的有价值的药物。在这里,我们报告发现一种新型有效的DPP-4抑制剂,其3 H-咪唑并[4,5- c ]喹啉4(5 H)-一个为骨架。使用对接研究对前导化合物2a在7位和8位进行高效优化后,我们发现28种新型DPP-4抑制剂具有对各种DPP-4同源物的优异选择性。化合物28与市售DPP-4抑制剂相比,具有较强的DPP-4抑制活性。我们还发现7位羧基可以与Lys554残基相互作用形成盐桥。另外,将羧基引入7位导致活性增强并且降低了hERG通道抑制和诱导的磷脂中毒的风险。在合成具有7个羧基的化合物时,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。

更新日期:2012-08-04
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