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  • br Results and discussion br Conclusion We have constructed


    Results and discussion
    Conclusion We have constructed a series of potent and greatly selective DPP-4 inhibitors with pyrazolo[1,5-a]pyrimidin-7(4H)-one core surrogates. The modification of the core led us to b2 which has IC50 of 80 nM and > 1000 fold selectivity over DPP-8 and DPP-9. We utilized docking program to study the interactions between the ligand and the enzyme. We discovered that in our model the substituted benzyl ring occupies the S1 pocket, and the amine substitution forms H-bond interactions with the key residue E205 and E206. Through the comparison of our model to the co-crystal structure 2NOC, this hypothesis came up that the core structure might have an impact on the ligand activity. Therefore we designed and synthesized d1 to redirect the core structure. As a result of this act the performance of the ligand improved immensely. Compound d1 has DPP-4 IC50 of 49 nM and more than 1000 fold selectivity over DPP8 and DPP-9. Although d1 has DPP-4 IC50 result greater than b2, yet b2 is considerably less cytotoxic. Further in vivo IPGTT assay further indicated that GSK1210151A b2 exert positive impact on the diabetic male mice. To sum up, we have identified a series of new derivatives as well potent DPP-4 inhibitors. Compounds b2 and d1 possess good DPP-4 inhibitory activity, remarkable selectivity over other DPP subtypes such as DPP-8 and DPP-9, low cytotoxicity, and excellent in vitro and in vivo efficacy. It produced a potential therapeutic efficacy for the treatment of type 2 diabetes.
    Experimental section
    Acknowledgments We thank the Medicine and Engineering interdisciplinary Research Fund of Shanghai Jiao Tong University (YG2015QN03, YG2014MS10 and YG2017MS77), National Natural Science Foundation of China (81202397) and Shanghai Natural Science Fund (12ZR1415400) for the financial support. We thank Professor Yongxiang Wang’s Laboratory (Shanghai Jiao Tong University) for the biological support of this research.
    We paid attentions on recently published paper by Lei and colleagues . The authors highlighted that DDP-4 inhibition with anagliptin contributed to atherosclerotic resistance. Intriguingly, the protective roles of DPP-4 inhibition during high glucose(HG)-/oscillating glucose(OG)-caused metabolic memory (MM) expanded their therapeutic effects , . It has been commonly indicated that early HG or OG was remembered despite tight glucose control on micro-/macro-vasculature that referred to MM , , and the mechanisms complied with persistent epigenetic modification , . Although our prior studies suggested that targeting histone demethylase KDM3A might limit MM-induced constant vascular remodeling , there existed great differences to transfer above achievements onto clinical trials. DPP-4 inhibitors such as vidagliptin and sitagliptin were well-acceptable anti-diabetic agents, which possessed vascular-favorable effects , . Recently, La and his coworkers confirmed that vildagliptin and sitagliptin were capable to compromise MM injury in human umbilical vein endothelial cells (HUVECs) via the oxidation/apoptosis-diminished manners. Similarly, teneligliptin, as a novel DPP-4 inhibitor, was demonstrated to revert HG-caused MM in HUVECs , in which the oxidation and apoptosis were markedly counteracted. These studies represented a promising step forward in understating MM occurrence, and more importantly, DDP-4 inhibitors use appeared to be implemented in the setting of diabetes to prevent the onset of MM.
    Introduction Diabetes is a common life-long health condition and a serious complex condition which can affect the entire body. In the last decade, the cases of people living with diabetes jumped almost 50 percent and worldwide, it afflicts more than 380million people. Dipeptidyl peptidase-IV (DPP-4) inhibitors, a newly emerging drug class for the treatment of type 2 diabetics. Dipeptidyl peptidase IV (DPP-4) is a protease enzyme which inactivates incretin hormones (Glucagon-like peptide 1 (GLP-1) and glucose dependent insulin tropic polypeptide (GIP)). Inhibiting DPP-4 prolongs the action of GLP-1 and GIP therefore DPP-4 inhibitors play important roles in maintaining glucose homeostasis [1]. Although the in vivo function of other members of DPP family, that is DPP-2, DPP-8, DPP-9 etc. are largely unknown the physiological effects of their inhibition has been documented in literature [2]. A number of catalytically active DPPs distinct from DPP-4 (DPP 2, FAP, DPP-8 and DPP-9) have been described that is associated with side-effects and toxicity [3]. Undergoing clinical trials on diabetic patients confirmed DPP-4 inhibitors as an add-on drug to oral hypoglycemic agents in type 2 diabetes. Sitagliptin was the first DPP-4 inhibitor granted by US-FDA for treating patients with type 2 diabetes followed by Vildagliptin, Saxagliptin and Linagliptin (Fig. 1) [4], [5]. Omarigliptin (MK-3102) (approved in Japan in 2015) can be used as once-weekly treatment and generally well-tolerated throughout the base and extension studies [6].