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Title: Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism

Abstract

Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4-and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t1/2 for dissociation ≈ 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Altogether, potent dipeptidyl peptidase inhibitionmay partially contribute to sustained efficacy of trelagliptin.

Authors:
ORCiD logo [1];  [2];  [1];  [3];  [3];  [4];  [4];  [5];  [5];  [5];  [1];  [3]
  1. Takeda California Inc., San Diego, CA (United States). Enzymology and Biophysical Chemistry
  2. Takeda California Inc., San Diego, CA (United States). Computational Sciences and Crystallography
  3. Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa (Japan). Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division
  4. Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa (Japan). Bio-Molecular Research Laboratories, Pharmaceutical Research Division
  5. Takeda Pharmaceutical Co. Ltd., Osaka (Japan). Takeda Development Center Japan
Publication Date:
Research Org.:
Takeda California Inc., San Diego, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1285963
Grant/Contract Number:  
AC03-76SF00098
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 11; Journal Issue: 6; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; double-blind; iv; alogliptin; complex; potent; discovery; profiles; rats; blood plasma; crystal structure; dogs; type 2 diabetes; chemical dissociation; diabetes mellitus; proteases; enzyme inhibitors

Citation Formats

Grimshaw, Charles E., Jennings, Andy, Kamran, Ruhi, Ueno, Hikaru, Nishigaki, Nobuhiro, Kosaka, Takuo, Tani, Akiyoshi, Sano, Hiroki, Kinugawa, Yoshinobu, Koumura, Emiko, Shi, Lihong, and Takeuchi, Koji. Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism. United States: N. p., 2016. Web. https://doi.org/10.1371/journal.pone.0157509.
Grimshaw, Charles E., Jennings, Andy, Kamran, Ruhi, Ueno, Hikaru, Nishigaki, Nobuhiro, Kosaka, Takuo, Tani, Akiyoshi, Sano, Hiroki, Kinugawa, Yoshinobu, Koumura, Emiko, Shi, Lihong, & Takeuchi, Koji. Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism. United States. https://doi.org/10.1371/journal.pone.0157509
Grimshaw, Charles E., Jennings, Andy, Kamran, Ruhi, Ueno, Hikaru, Nishigaki, Nobuhiro, Kosaka, Takuo, Tani, Akiyoshi, Sano, Hiroki, Kinugawa, Yoshinobu, Koumura, Emiko, Shi, Lihong, and Takeuchi, Koji. Tue . "Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism". United States. https://doi.org/10.1371/journal.pone.0157509. https://www.osti.gov/servlets/purl/1285963.
@article{osti_1285963,
title = {Trelagliptin (SYR-472, Zafatek), novel once-weekly treatment for type 2 diabetes, inhibits dipeptidyl peptidase-4 (DPP-4) via a non-covalent mechanism},
author = {Grimshaw, Charles E. and Jennings, Andy and Kamran, Ruhi and Ueno, Hikaru and Nishigaki, Nobuhiro and Kosaka, Takuo and Tani, Akiyoshi and Sano, Hiroki and Kinugawa, Yoshinobu and Koumura, Emiko and Shi, Lihong and Takeuchi, Koji},
abstractNote = {Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4-and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t1/2 for dissociation ≈ 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Altogether, potent dipeptidyl peptidase inhibitionmay partially contribute to sustained efficacy of trelagliptin.},
doi = {10.1371/journal.pone.0157509},
journal = {PLoS ONE},
number = 6,
volume = 11,
place = {United States},
year = {2016},
month = {6}
}

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Works referenced in this record:

SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial
journal, February 2014


The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes
journal, November 2006


DPP-4 inhibitors: pharmacological differences and their clinical implications
journal, August 2014

  • Ceriello, Antonio; Sportiello, Liberata; Rafaniello, Concetta
  • Expert Opinion on Drug Safety, Vol. 13, Issue sup1
  • DOI: 10.1517/14740338.2014.944862

Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study
journal, March 2015


Characterization of dipeptidyl and tripeptidyl aminopeptidases in human kidney soluble fraction
journal, February 1991


The determination of enzyme inhibitor constants
journal, August 1953


A fully integrated protein crystallization platform for small-molecule drug discovery
journal, April 2003


The CCP4 suite programs for protein crystallography
journal, September 1994


XtalView/Xfit—A Versatile Program for Manipulating Atomic Coordinates and Electron Density
journal, April 1999


Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys
journal, July 2008


Design and Synthesis of Pyrimidinone and Pyrimidinedione Inhibitors of Dipeptidyl Peptidase IV
journal, January 2011

  • Zhang, Zhiyuan; Wallace, Michael B.; Feng, Jun
  • Journal of Medicinal Chemistry, Vol. 54, Issue 2
  • DOI: 10.1021/jm101016w

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

  • Feng, Jun; Zhang, Zhiyuan; Wallace, Michael B.
  • Journal of Medicinal Chemistry, Vol. 50, Issue 10
  • DOI: 10.1021/jm070104l

Mechanism of Gly-Pro-pNA cleavage catalyzed by dipeptidyl peptidase-IV and its inhibition by saxagliptin (BMS-477118)
journal, January 2006

  • Kim, Young B.; Kopcho, Lisa M.; Kirby, Mark S.
  • Archives of Biochemistry and Biophysics, Vol. 445, Issue 1
  • DOI: 10.1016/j.abb.2005.11.010

Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation
journal, February 2008

  • Metzler, William J.; Yanchunas, Joseph; Weigelt, Carolyn
  • Protein Science, Vol. 17, Issue 2
  • DOI: 10.1110/ps.073253208

High-resolution structure of human apo dipeptidyl peptidase IV/CD26 and its complex with 1-[({2-[(5-iodopyridin-2-yl)amino]-ethyl}amino)-acetyl]-2-cyano-( S )-pyrrolidine
journal, June 2003

  • Oefner, Christian; D'Arcy, Allan; Mac Sweeney, Aengus
  • Acta Crystallographica Section D Biological Crystallography, Vol. 59, Issue 7
  • DOI: 10.1107/S0907444903010059

Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited
journal, November 2008


Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor
journal, July 2009


    Works referencing / citing this record:

    Different Spectrophotometric Methods for Simultaneous Determination of Trelagliptin and Its Acid Degradation Product
    journal, January 2018

    • Mowaka, Shereen; Ayoub, Bassam M.; Hassan, Mostafa A.
    • Journal of Analytical Methods in Chemistry, Vol. 2018
    • DOI: 10.1155/2018/7370651

    Once-weekly dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a systematic review and meta-analysis
    text, January 2017