A novel DPP-4 inhibitor teneligliptin scavenges hydroxyl radicals: In vitro study evaluated by electron spin resonance spectroscopy and in vivo study using DPP-4 deficient rats

Aims. Recently various dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged because of their high effectiveness and safety. In spite of their common effect of DPP-4 inhibition, the chemical structures are diverse. Here we show that the structure of teneligliptin, a novel DPP-4 inhibitor, has a scavenging activity on hydroxyl radical (center dot OH). Methods. center dot OH and superoxide (O-2(-)) were detected by electron spin resonance (ESR) spectroscopy. center dot OH and O-2(-) were generated in vitro by the Fenton reaction and a hypoxanthine-xanthine oxidase system, respectively. The level of free radicals was estimated from the ESR signal intensity. The product via teneligliptin and center dot OH reaction was identified by thin layer chromatography and mass spectrometry analysis. In vivo effect was also evaluated using DPP-4 deficient rats with streptozotocin-induced diabetes. Results. ESR spectroscopy analysis showed that teneligliptin did not scavenge O-2(-), but scavenged center dot OH in a dose dependent manner. Its activity was greater than that of glutathione. The reaction product appeared to have an oxygen-atom added structure to that of teneligliptin, which was identical to the most abundant metabolite of teneligliptin in human plasma. Furthermore, using DPP-4 deficient rat, teneligliptin did not affect plasma glucose levels or body weight, but normalized increased levels of 8-hydroxy-2'-deoxyguanosine in urine, kidney and aorta of diabetic rats, supporting that teneligliptin may have a center dot OH scavenging activity in vivo independently of DPP-4 inhibition. Conclusions. Teneligliptin is not only effective as DPP-4 inhibitor, but may also be beneficial as center dot OH scavenger, which may be useful in the prevention of diabetic complications. (C) 2015 Elsevier Inc. All rights reserved.