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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

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 (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.

Authors:
ORCiD logo [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:
Research Org.:
Takeda California Inc., San Diego, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1285963
Grant/Contract Number:
AC03-76SF00098
Resource Type:
Journal Article: 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. 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, and Takeuchi, Koji. 2016. "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. doi: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 = 2016,
month = 6
}

Journal Article:
Free Publicly Available Full Text
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Cited by: 2works
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  • In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
  • A novel series of {beta}-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC{sub 50} = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.
  • Highlights: •DPP-4 inhibitor decreased urinary albumin excretion in a rat of type 1 diabetes. •DPP-4 inhibitor ameliorated histlogical changes of diabetic nephropathy. •DPP-4 inhibitor has reno-protective effects through anti-inflammatory action. •DPP-4 inhibitor is beneficial on diabetic nephropathy besides lowering blood glucose. -- Abstract: Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbationmore » of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. Materials and methods: Five-week-old male Sprague–Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. Results: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. Conclusions: These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.« less