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

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

doi:10.1371/journal.pone.0157509

Title: 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 · Tue Jun 21 00:00:00 EDT 2016 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0157509· OSTI ID:1285963

^[1]; Jennings, Andy ^[2]; Kamran, Ruhi ^[1]; Ueno, Hikaru ^[3]; Nishigaki, Nobuhiro ^[3]; Kosaka, Takuo ^[4]; Tani, Akiyoshi ^[4]; Sano, Hiroki ^[5]; Kinugawa, Yoshinobu ^[5]; Koumura, Emiko ^[5]; Shi, Lihong ^[1]; Takeuchi, Koji ^[3]

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

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 (t_1/2 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.

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Research Organization:: Takeda California Inc., San Diego, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC03-76SF00098

OSTI ID:: 1285963

Journal Information:: PLoS ONE, Vol. 11, Issue 6; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 32 works

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Once-weekly dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a systematic review and meta-analysis Stoimenis, Dimitrios; Karagiannis, Thomas; Katsoula, Anastasia Taylor & Francis https://doi.org/10.6084/m9.figshare.4988000.v1	text	January 2017

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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

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