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.
- Authors:
-
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Lead Optimization Chemistry
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Structural Chemistry
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Structural Chemistry
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Department of Pharmacology
- Merck Research Lab., Kenilworth, NJ (United States). Dept. of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1404985
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- ACS Medicinal Chemistry Letters
- Additional Journal Information:
- Journal Volume: 7; Journal Issue: 5; Journal ID: ISSN 1948-5875
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Redox reactions; Carbohydrates; Scaffolds; Inhibitors; Inhibition; Diabetes; dipeptidyl peptidase IV (DPP-4); inhibitor tricyclic heterocycles; crystal structure; OGTT
Citation Formats
Wu, Wen-Lian, Hao, Jinsong, Domalski, Martin, Burnett, Duane A., Pissarnitski, Dmitri, Zhao, Zhiqiang, Stamford, Andrew, Scapin, Giovanna, Gao, Ying-Duo, Soriano, Aileen, Kelly, Terri M., Yao, Zuliang, Powles, Mary Ann, Chen, Shiying, Mei, Hong, and Hwa, Joyce. Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes. United States: N. p., 2016.
Web. doi:10.1021/acsmedchemlett.6b00027.
Wu, Wen-Lian, Hao, Jinsong, Domalski, Martin, Burnett, Duane A., Pissarnitski, Dmitri, Zhao, Zhiqiang, Stamford, Andrew, Scapin, Giovanna, Gao, Ying-Duo, Soriano, Aileen, Kelly, Terri M., Yao, Zuliang, Powles, Mary Ann, Chen, Shiying, Mei, Hong, & Hwa, Joyce. Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes. United States. https://doi.org/10.1021/acsmedchemlett.6b00027
Wu, Wen-Lian, Hao, Jinsong, Domalski, Martin, Burnett, Duane A., Pissarnitski, Dmitri, Zhao, Zhiqiang, Stamford, Andrew, Scapin, Giovanna, Gao, Ying-Duo, Soriano, Aileen, Kelly, Terri M., Yao, Zuliang, Powles, Mary Ann, Chen, Shiying, Mei, Hong, and Hwa, Joyce. 2016.
"Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes". United States. https://doi.org/10.1021/acsmedchemlett.6b00027. https://www.osti.gov/servlets/purl/1404985.
@article{osti_1404985,
title = {Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes},
author = {Wu, Wen-Lian and Hao, Jinsong and Domalski, Martin and Burnett, Duane A. and Pissarnitski, Dmitri and Zhao, Zhiqiang and Stamford, Andrew and Scapin, Giovanna and Gao, Ying-Duo and Soriano, Aileen and Kelly, Terri M. and Yao, Zuliang and Powles, Mary Ann and Chen, Shiying and Mei, Hong and Hwa, Joyce},
abstractNote = {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.},
doi = {10.1021/acsmedchemlett.6b00027},
url = {https://www.osti.gov/biblio/1404985},
journal = {ACS Medicinal Chemistry Letters},
issn = {1948-5875},
number = 5,
volume = 7,
place = {United States},
year = {Tue Mar 15 00:00:00 EDT 2016},
month = {Tue Mar 15 00:00:00 EDT 2016}
}
Web of Science
Figures / Tables:
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Works referencing / citing this record:
Emergence of promising novel DPP-4 inhibitory heterocycles as anti-diabetic agents: A review
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Figures / Tables found in this record: