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.
Highlights
MethodsChemicalsAlogliptin (2-[6-(3(R)-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin1-ylmethyl]benzonitrile), trelagliptin (2-[6-(3(R)-aminopiperidin-1-yl)-3-methyl-2,4-dioxo3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile), and sitagliptin ((2R)-4-oxo-4[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophe nyl)butan-2-amine) were synthesized at Takeda Pharmaceutical Company Limited
Nmol/L for trelagliptin and alogliptin, respectively). These results suggest that the potent in vitro Dipeptidyl peptidase-4 (DPP-4) inhibitory activity of trelagliptin at least partially contributes to the in vivo efficacy of trelagliptin at lower plasma concentration at 7 days after administration
We demonstrated that trelagliptin shows > 10,000-fold selectivity for DPP-4 over other related serine proteases including dipeptidyl peptidase-8 (DPP-8) and dipeptidyl peptidase-9 (DPP-9)
Summary
ChemicalsAlogliptin (2-[6-(3(R)-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin1-ylmethyl]benzonitrile), trelagliptin (2-[6-(3(R)-aminopiperidin-1-yl)-3-methyl-2,4-dioxo3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile), and sitagliptin ((2R)-4-oxo-4[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophe nyl)butan-2-amine) were synthesized at Takeda Pharmaceutical Company Limited. All animals were housed in cages in a room with controlled temperature (23°C), humidity (55%) and lighting (lights on from 07:30 am to 07:30 pm) and were maintained on a laboratory chow diet (CE2 [CLEA Japan] for rats and DS-5 [Oriental Yeast Co., Ltd.] for dogs). Rat blood samples were taken from abdominal vein under ether inhalation anesthesia in anesthetized rats before euthanasia by exsanguination. Dog blood samples were collected from anterior limb veins in conscious dogs that were restrained in a retainer. Dogs were returned to their normal housing for other experiments.
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