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

ABSTRACT: 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.

SUBMITTER: Wu WL

PROVIDER: S-EPMC4867478 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Wu Wen-Lian WL Hao Jinsong J Domalski Martin M Burnett Duane A DA Pissarnitski Dmitri D Zhao Zhiqiang Z Stamford Andrew A Scapin Giovanna G Gao Ying-Duo YD Soriano Aileen A Kelly Terri M TM Yao Zuliang Z Powles Mary Ann MA Chen Shiying S Mei Hong H Hwa Joyce J

ACS medicinal chemistry letters 20160312 5

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 ...[more]

PMID: 27190600

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