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. Taken together, potent dipeptidyl peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.
Enzymology and Biophysical Chemistry, Takeda California, Inc., San Diego, California, United States of America.
Charles E
http://orcid.org/0000-0002-2897-3483
CE
Grimshaw
Computational Sciences and Crystallography, Takeda California, Inc., San Diego, California, United States of America.
Andy
A
Jennings
Enzymology and Biophysical Chemistry, Takeda California, Inc., San Diego, California, United States of America.
Ruhi
R
Kamran
Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Hikaru
H
Ueno
Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Nobuhiro
N
Nishigaki
Bio-Molecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Takuo
T
Kosaka
Bio-Molecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Akiyoshi
A
Tani
Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
Hiroki
H
Sano
Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
Yoshinobu
Y
Kinugawa
Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
Emiko
E
Koumura
Enzymology and Biophysical Chemistry, Takeda California, Inc., San Diego, California, United States of America.
Lihong
L
Shi
Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Koji
K
Takeuchi
D000818:Animals; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D006801:Humans; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D000068900:Sitagliptin Phosphate / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects; D013997:Time Factors; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D014498:Uracil; D018819:Dipeptidyl Peptidase 4; C520853:alogliptin; C000595449:trelagliptin; D000068900:Sitagliptin Phosphate