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  • Diabetic retinopathy is a chronic inflammatory disease Local


    Diabetic retinopathy is a chronic inflammatory disease. Local inflammation plays a pivotal role in the pathological development and progression of this disease [24]. In addition to TNF-α, several other cytokines, chemokines, and other factors such as IL-1β, IL-6, and C-reactive protein have been indicated to be associated with the pathophysiology and the microvascular complications of diabetic retinopathy. These factors are elevated in the retina and vitreous of diabetic patients and animal models of diabetes [25]. In this study, we found that linagliptin treatment significantly reduced TNF-α-induced expression and secretion of IL-6 and IL-8. We also investigated the effects of linagliptin on IL-1β-induced insults in endothelial cells. Consistent results were found which displayed that linagliptin possesses a protective effect against IL-1β-induced THP-1 adhesion to retinal endothelial cells (RECs) (Results not shown). In the future, the synergistic contributions of redox-inflammatory processes for endothelial dysfunction in diabetic retinopathy are should be examined. The following are the supplementary data related to this article.
    Acknowledgement This project was supported by Sichuan Provincial Health and Family Planning Commission (No. 17PJ551).
    Introduction Type 2 diabetes is one of the greatest impending global health concerns. To date 415 million people live with diabetes worldwide, and an estimated 193 million people have undiagnosed diabetes. Type 2 diabetes accounts for more than 90% of diabetes patients. Progressing efforts regarding risk factors for type 2 diabetes and some prevention programs have been proved to be resultful. But the incidence and widespread occurrence of the disease continues to rise globally and more than twofold increase is expected over next 20 years. Among all discovered paths, the incretin pathway is emerging as a promising target for diabetes treatment. It facilitates a communication channel between the intestine and the endocrine pancreas and accounts for 50–70% of the total β cell derived insulin secretion in response to oral glucose ingestion. In fact, incretin-receptor activation is mainly occurred by glucagon like peptide-1 (GLP-1), one of the key hormones of this mechanism. GLP-1 stimulates the secretion of insulin after oral glucose PIK-III and as a result normalizes the blood glucose level. On the other side, incretin is inactivated by the enzyme dipeptidyl peptidase (DPP-4) through catalyzing the hydrolization of GLP-1. Therefore, therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes. For instance, the development of degradation-resistant GLP-1–receptor agonists or DPP-4 inhibitors would lead to increase plasma concentration of active GLP-1. On recent advances in drug discovery, a variety of DPP-4 inhibitors with diverse structural features has been created as anti-diabetic drugs. Unfortunately, the currently available DPP-4 inhibitors, as shown in Fig. 1, are inevitably associated with several side effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. These side effects are caused due to the off-target effect: the inhibition of other DPP subtypes such as DPP-8 and DPP-9. To avoid those side effects, it’s necessary to design advanced inhibitors with high activity for DPP-4 and great selectivity against other DPP subtypes as well. Pyrazolo[1,5-a]pyrimidin derivatives are wildly used in pharmaceutical industries6, 7, 8 and academic researches9, 10, 11, 12, 13 as lead compounds for the discovery of potential medical agents. However, they were never utilized as anti-diabetic candidates. The current study outlined the new approach towards creating a new series of DPP-4 inhibitors, with a focus on rational drug design and structural optimization to pursue high in vitro activity, high selectivity and low cytotoxicity. To earn these benefits, we executed two strategies to generate new inhibitors as outlined in Fig. 2. Firstly, we aimed to generate new class ligands by applying a novel core structure. By analyzing the structural components of the DPP-4 inhibitors, we found that the two key building blocks should be standing adjacent to each other with a distance of 1–2 atoms.14, 15 It suggests that the positions of the substitutions are important for activity. The skeleton of pyrazolo[1,5-a]pyrimidin-7(4H)-one perfectly meets the demand of such structural requirement, where substitutions can be attached to multiple contiguous positions. The π-π stacking between the core structure and Y547 would hopefully stabilize the overall conformation. We then constructed 4, 5-substituted pyrazolo[1,5-a]pyrimidin-7(4H)-one analogs and discovered a novel series of DPP-4 inhibitors. Secondly, we study the nature of key building blocks. A hydrophobic or aromatic ring is needed to occupy the S1 pocket of DPP-4.17, 18, 19, 20 The salt bridge between the ligand and E205/E206 residues plays a significant role for the generation of inhibition activity.16, 21 Based on such findings, we designed compounds with a substituted benzyl group on 4′ position for the S1 occupation; and a cyclic amine group on 5′ position for salt bridge networking. This approach could yield a unique series of DPP-4 inhibitors.