Open AccessDiscovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes
Author(s) -
WenLian Wu,
Jinsong Hao,
Martin S. Domalski,
Duane A. Burnett,
Dmitri Pissarnitski,
Zhiqiang Zhao,
Andrew W. Stamford,
Giovanna Scapin,
YingDuo Gao,
Aileen Soriano,
Terri Kelly,
Zuliang Yao,
Mary Ann Powles,
Shiying Chen,
Mei Hong,
Joyce Hwa
Publication year - 2016
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.6b00027
Subject(s) - alogliptin , tricyclic , cocrystal , drug discovery , sitagliptin , combinatorial chemistry , chemistry , scaffold , pharmacology , type 2 diabetes , computational biology , computer science , medicine , diabetes mellitus , stereochemistry , molecule , biochemistry , biology , hydrogen bond , endocrinology , organic chemistry , database
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.