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:
-
[1];
- Takeda California Inc., San Diego, CA (United States). Enzymology and Biophysical Chemistry
- Takeda California Inc., San Diego, CA (United States). Computational Sciences and Crystallography
- Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa (Japan). Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division
- Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa (Japan). Bio-Molecular Research Laboratories, Pharmaceutical Research Division
- 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. doi: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 = {Tue Jun 21 00:00:00 EDT 2016},
month = {Tue Jun 21 00:00:00 EDT 2016}
}
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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
- Inagaki, Nobuya; Onouchi, Hitoshi; Sano, Hiroki
- The Lancet Diabetes & Endocrinology, Vol. 2, Issue 2
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes
journal, November 2006
- Drucker, Daniel J.; Nauck, Michael A.
- The Lancet, Vol. 368, Issue 9548
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
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
- Inagaki, Nobuya; Onouchi, Hitoshi; Maezawa, Hideaki
- The Lancet Diabetes & Endocrinology, Vol. 3, Issue 3
TMC-2A, -2B and -2C, Novel Dipeptidyl Peptidase IV Inhibitors Produced by Aspergillus oryzae A374. I.Taxonomy of Producing Strains, Fermentation, and Biochemical Properties.
journal, January 1997
- Nonaka, Nobuaki; Asai, Yasuyuki; Nishio, Maki
- The Journal of Antibiotics, Vol. 50, Issue 8
Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation
journal, February 2004
- Aertgeerts, K.
- Protein Science, Vol. 13, Issue 2
Effect of a Novel Prolyl Endopeptidase Inhibitor, JTP-4819, on Prolyl Endopeptidase Activity and Substance P- and Arginine-Vasopressin-Like Immunoreactivity in the Brains of Aged Rats
journal, July 1995
- Toide, Katsuo; Okamiya, Kazuhiro; Iwamoto, Yohko
- Journal of Neurochemistry, Vol. 65, Issue 1
The determination of enzyme inhibitor constants
journal, August 1953
- Dixon, M.
- Biochemical Journal, Vol. 55, Issue 1
A fully integrated protein crystallization platform for small-molecule drug discovery
journal, April 2003
- Hosfield, David; Palan, John; Hilgers, Mark
- Journal of Structural Biology, Vol. 142, Issue 1
The CCP4 suite programs for protein crystallography
journal, September 1994
- ,
- Acta Crystallographica Section D Biological Crystallography, Vol. 50, Issue 5, p. 760-763
XtalView/Xfit—A Versatile Program for Manipulating Atomic Coordinates and Electron Density
journal, April 1999
- McRee, Duncan E.
- Journal of Structural Biology, Vol. 125, Issue 2-3
Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys
journal, July 2008
- Lee, Bumsup; Shi, Lihong; Kassel, Daniel B.
- European Journal of Pharmacology, Vol. 589, Issue 1-3
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
(2 R )-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin- 7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes
journal, January 2005
- Kim, Dooseop; Wang, Liping; Beconi, Maria
- Journal of Medicinal Chemistry, Vol. 48, Issue 1
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
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
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
Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile)
journal, July 2005
- Brandt, Inger; Joossens, Jurgen; Chen, Xin
- Biochemical Pharmacology, Vol. 70, Issue 1
Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: A randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes
journal, March 2008
- Covington, P.; Christopher, R.; Davenport, M.
- Clinical Therapeutics, Vol. 30, Issue 3
Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes: Potential Importance of Selectivity Over Dipeptidyl Peptidases 8 and 9
journal, September 2005
- Lankas, G. R.; Leiting, B.; Roy, R. S.
- Diabetes, Vol. 54, Issue 10
Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited
journal, November 2008
- Burkey, B. F.; Hoffmann, P. K.; Hassiepen, U.
- Diabetes, Obesity and Metabolism, Vol. 10, Issue 11
Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor
journal, July 2009
- Wu, Jia-Jing; Tang, Hung-Kuan; Yeh, Teng-Kuang
- Biochemical Pharmacology, Vol. 78, Issue 2
Characterization of dipeptidyl and tripeptidyl aminopeptidases in human kidney soluble fraction
journal, February 1991
- Mantle, David
- Clinica Chimica Acta, Vol. 196, Issue 2-3
Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile)
journal, July 2005
- Brandt, Inger; Joossens, Jurgen; Chen, Xin
- Biochemical Pharmacology, Vol. 70, Issue 1
Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: A randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes
journal, March 2008
- Covington, P.; Christopher, R.; Davenport, M.
- Clinical Therapeutics, Vol. 30, Issue 3
Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys
journal, July 2008
- Lee, Bumsup; Shi, Lihong; Kassel, Daniel B.
- European Journal of Pharmacology, Vol. 589, Issue 1-3
The importance of incretin therapies for managing type 2 diabetes
journal, February 2014
- Garber, Alan J.
- The Lancet Diabetes & Endocrinology, Vol. 2, Issue 2
Once-weekly DPP-4 inhibitors: do they meet an unmet need?
journal, March 2015
- Scheen, André J.
- The Lancet Diabetes & Endocrinology, Vol. 3, Issue 3
(2 R )-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin- 7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes
journal, January 2005
- Kim, Dooseop; Wang, Liping; Beconi, Maria
- Journal of Medicinal Chemistry, Vol. 48, Issue 1
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
Effect of a Novel Prolyl Endopeptidase Inhibitor, JTP-4819, on Prolyl Endopeptidase Activity and Substance P- and Arginine-Vasopressin-Like Immunoreactivity in the Brains of Aged Rats
journal, July 1995
- Toide, Katsuo; Okamiya, Kazuhiro; Iwamoto, Yohko
- Journal of Neurochemistry, Vol. 65, Issue 1
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
Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited
journal, November 2008
- Burkey, B. F.; Hoffmann, P. K.; Hassiepen, U.
- Diabetes, Obesity and Metabolism, Vol. 10, Issue 11
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
TMC-2A, -2B and -2C, Novel Dipeptidyl Peptidase IV Inhibitors Produced by Aspergillus oryzae A374. I.Taxonomy of Producing Strains, Fermentation, and Biochemical Properties.
journal, January 1997
- Nonaka, Nobuaki; Asai, Yasuyuki; Nishio, Maki
- The Journal of Antibiotics, Vol. 50, Issue 8
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
Once-weekly dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a systematic review and meta-analysis
text, January 2017
- Stoimenis, Dimitrios; Karagiannis, Thomas; Katsoula, Anastasia
- Taylor & Francis
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