期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 7, 期 5, 页码 498-501出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00027
关键词
Diabetes; dipeptidyl peptidase IV (DPP-4); inhibitor; tricyclic heterocycles; crystal structure; OGTT
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.
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