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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

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.
 [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:
OSTI Identifier:
Grant/Contract Number:
Accepted Manuscript
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Additional Journal Information:
Journal Volume: 11; Journal Issue: 6; Journal ID: ISSN 1932-6203
Public Library of Science
Research Org:
Takeda California Inc., San Diego, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
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