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.
MeSH terms
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Animals
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Crystallography, X-Ray
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / enzymology*
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Dipeptidyl Peptidase 4 / chemistry
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Dipeptidyl Peptidase 4 / metabolism
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology
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Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
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Dogs
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Humans
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Male
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Piperidines / pharmacology
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Rats, Sprague-Dawley
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Sitagliptin Phosphate / pharmacology
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Substrate Specificity / drug effects
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Time Factors
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Uracil / analogs & derivatives*
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Uracil / pharmacology
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Uracil / therapeutic use
Substances
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Dipeptidyl-Peptidase IV Inhibitors
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Piperidines
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Uracil
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Dipeptidyl Peptidase 4
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alogliptin
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trelagliptin
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Sitagliptin Phosphate
Grants and funding
During the time this work was conducted, each of the co-authors was an employee of the global Takeda Pharmaceutical Company Limited or one of its wholly owned affiliates, which provided support in the form of salaries for authors [CEG, AJ, RK, HU, NN, TK, AT, HS, YK, EK, LS, and KT], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.