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

Journal Article · · PLoS ONE
 [1];  [2];  [3];  [4];  [4];  [5];  [5];  [6];  [6];  [6];  [3];  [4]
  1. Takeda California Inc., San Diego, CA (United States). Enzymology and Biophysical Chemistry; 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 California Inc., San Diego, CA (United States). Enzymology and Biophysical Chemistry
  4. Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa (Japan). Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division
  5. Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa (Japan). Bio-Molecular Research Laboratories, Pharmaceutical Research Division
  6. Takeda Pharmaceutical Co. Ltd., Osaka (Japan). Takeda Development Center Japan
+ Show Author Affiliations

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.

Research Organization:
Takeda California Inc., San Diego, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
AC03-76SF00098
OSTI ID:
1285963
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 6 Vol. 11; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

References (30)

Characterization of dipeptidyl and tripeptidyl aminopeptidases in human kidney soluble fraction journal February 1991
Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile) journal July 2005
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
Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys journal July 2008
Gliptins journal January 2007
A fully integrated protein crystallization platform for small-molecule drug discovery journal April 2003
The importance of incretin therapies for managing type 2 diabetes journal February 2014
Once-weekly DPP-4 inhibitors: do they meet an unmet need? journal March 2015
(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
Discovery of Alogliptin:  A Potent, Selective, Bioavailable, and Efficacious Inhibitor of Dipeptidyl Peptidase IV † journal May 2007
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
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
Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited journal November 2008
DPP-4 inhibitors: pharmacological differences and their clinical implications journal August 2014
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
XtalView/Xfit—A Versatile Program for Manipulating Atomic Coordinates and Electron Density journal April 1999
Characterization of dipeptidyl and tripeptidyl aminopeptidases in human kidney soluble fraction journal February 1991
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes journal November 2006
A fully integrated protein crystallization platform for small-molecule drug discovery journal April 2003
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
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
Mechanism of Gly-Pro-pNA cleavage catalyzed by dipeptidyl peptidase-IV and its inhibition by saxagliptin (BMS-477118) journal January 2006
Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor journal July 2009
Design and Synthesis of Pyrimidinone and Pyrimidinedione Inhibitors of Dipeptidyl Peptidase IV journal January 2011
The determination of enzyme inhibitor constants journal August 1953
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
The CCP4 suite programs for protein crystallography journal September 1994
Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation journal February 2004
Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation journal February 2008
Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes: Potential Importance of Selectivity Over Dipeptidyl Peptidases 8 and 9 journal September 2005

Cited By (2)

Different Spectrophotometric Methods for Simultaneous Determination of Trelagliptin and Its Acid Degradation Product journal January 2018
Once-weekly dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a systematic review and meta-analysis text January 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
alogliptin
blood plasma
chemical dissociation
complex
crystal structure
diabetes mellitus
discovery
dogs
double-blind
enzyme inhibitors
iv
potent
profiles
proteases
rats
type 2 diabetes