Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes

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• 作者：Wen-Lian Wu ; Jinsong Hao ; Martin Domalski ; Duane A. Burnett ; Dmitri Pissarnitski ; Zhiqiang Zhao ; Andrew Stamford ; Giovanna Scapin ; Ying-Duo Gao ; Aileen Soriano ; Terri M. Kelly ; Zuliang Yao ; Mary Ann Powles ; Shiying Chen ; Hong Mei ; Joyce Hwa
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：May 12, 2016
• 年：2016
• 卷：7
• 期：5
• 页码：498-501
• 全文大小：338K
• 年卷期：0
• ISSN：1948-5875

文摘

In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.