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Title: 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:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [4];  [4];  [4];  [4];  [5];  [5];  [4]
  1. Merck Research Lab., Kenilworth, NJ (United States). Dept. of Lead Optimization Chemistry
  2. Merck Research Lab., Kenilworth, NJ (United States). Dept. of Structural Chemistry
  3. Merck Research Lab., Kenilworth, NJ (United States). Dept. of Structural Chemistry
  4. Merck Research Lab., Kenilworth, NJ (United States). Dept. of Department of Pharmacology
  5. 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}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 24 works
Citation information provided by
Web of Science

Figures / Tables:

Figure 1 Figure 1: Representative DPP-4 inhibitors

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Works referenced in this record:

Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes
journal, January 2008


Discovery of Potent and Selective Dipeptidyl Peptidase IV Inhibitors Derived from β-Aminoamides Bearing Subsituted Triazolopiperazines
journal, January 2008


Omarigliptin (MK-3102): A Novel Long-Acting DPP-4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes
journal, April 2014


Discovery of Alogliptin:  A Potent, Selective, Bioavailable, and Efficacious Inhibitor of Dipeptidyl Peptidase IV
journal, May 2007


9-Benzyl-6-(dimethylamino)-9H-purines with antirhinovirus activity
journal, October 1988


A short, versatile synthesis of porphobilinogen
journal, January 1976


Prolyl peptidases: a serine protease subfamily with high potential for drug discovery
journal, August 2003


Purification, identification and characterisation of seprase from bovine serum
journal, November 2004


Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8: A novel dipeptidyl peptidase
journal, October 2000


Works referencing / citing this record:

Emergence of promising novel DPP-4 inhibitory heterocycles as anti-diabetic agents: A review
journal, June 2018


Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening
journal, April 2018


Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.