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

被引：36

作者：

Wu, Wen-Lian ^{[1
]}

Hao, Jinsong ^{[1
]}

Domalski, Martin ^{[1
]}

Burnett, Duane A. ^{[1
]}

Pissarnitski, Dmitri ^{[1
]}

Zhao, Zhiqiang ^{[1
]}

Stamford, Andrew ^{[1
]}

Scapin, Giovanna ^{[2
]}

Gao, Ying-Duo ^{[2
]}

Soriano, Aileen ^{[3
]}

Kelly, Terri M. ^{[3
]}

Yao, Zuliang ^{[3
]}

Powles, Mary Ann ^{[3
]}

Chen, Shiying ^{[4
]}

Mei, Hong ^{[4
]}

Hwa, Joyce ^{[3
]}

机构：

[1] Merck Res Labs, Dept Lead Optimizat Chem, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[2] Merck Res Labs, Dept Struct Chem, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[3] Merck Res Labs, Dept Pharmacol, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[4] Merck Res Labs, Dept Pharmacokinet Pharmacodynam & Drug Metab, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 05期

关键词：

Diabetes; dipeptidyl peptidase IV (DPP-4); inhibitor; tricyclic heterocycles; crystal structure; OGTT; DIPEPTIDYL-PEPTIDASE-IV; IDENTIFICATION; HOMOLOG; CLONING;

D O I：

10.1021/acsmedchemlett.6b00027

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：498 / 501

页数：4

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