Trelagliptin (SYR-472, Zafatek), Novel Once-Weekly Treatment for Type 2 Diabetes, Inhibits Dipeptidyl Peptidase-4 (DPP-4) via a Non-Covalent Mechanism

  • PLoS One. 2016 Jun 21;11(6):e0157509. doi: 10.1371/journal.pone.0157509.
Charles E Grimshaw  1 ,  Andy Jennings  2 ,  Ruhi Kamran  1 ,  Hikaru Ueno  3 ,  Nobuhiro Nishigaki  3 ,  Takuo Kosaka  4 ,  Akiyoshi Tani  4 ,  Hiroki Sano  5 ,  Yoshinobu Kinugawa  5 ,  Emiko Koumura  5 ,  Lihong Shi  1 ,  Koji Takeuchi  3
Affiliations
  • 1. Enzymology and Biophysical Chemistry, Takeda California, Inc., San Diego, California, United States of America.
  • 2. Computational Sciences and Crystallography, Takeda California, Inc., San Diego, California, United States of America.
  • 3. Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 4. Bio-Molecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 5. Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
PMID: 27328054 DOI: 10.1371/journal.pone.0157509
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. Taken together, potent Dipeptidyl Peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.

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