Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions

Watanabe, Yukihisa S.; Yasuda, Yoshika; Kojima, Yoshitaka; Okada, Shino; Motoyama, Tomoko; Takahashi, Ryo; Oka, Mitsuru

doi:10.3109/14756366.2014.1002402

Cited by 39 publications

(33 citation statements)

References 32 publications

(37 reference statements)

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“…DPP‐4 inhibitors, such as anagliptin, inhibit the extracellular catalytic domain of DPP‐4,21 preventing the degradation of substrates including stromal cell–derived factor 122 and platelet‐activating factor 23. Soluble DPP‐4, shed from the cell surface, lacks the cytoplasmic and transmembrane domains but has preserved catalytic capacity.…”

Section: Discussionmentioning

confidence: 99%

“…The catalytic region in the C-terminal extracellular domain is responsible for the dipeptidase activity on substrate peptides including incretins, neuropeptides, chemokines, and cytokines. 20 DPP-4 inhibitors, such as anagliptin, inhibit the extracellular catalytic domain of DPP-4, 21 preventing the degradation of substrates including stromal cell-derived factor 1 22 and Figure 3. Anagliptin treatment inhibits the inflammatory activation of RAW264.7 macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Ikedo

Minami

Kataoka

et al. 2017

JAHA

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BackgroundChronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model.Methods and Results IAs were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP‐1 and IL‐6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro.ConclusionsA DPP‐4 inhibitor, anagliptin, prevents the growth of IAs via its anti‐inflammatory effects on macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Ikedo

Minami

Kataoka

et al. 2017

JAHA

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“…DPP‐4 inhibitors are characterized by diverse chemical structures, suggesting different interactions in the enzyme active site. Binding modes of approved inhibitors (vildagliptin, saxagliptin, alogliptin, linagliptin, sitagliptin, gemigliptin, anagliptin, and teneligliptin) (Figure ) with the enzyme have been determined and comparative studies have been reported …”

Section: Dipeptidyl Peptidase‐4 and Its Clinically Used Inhibitorsmentioning

confidence: 99%

“…Alogliptin and linagliptin, Class 2 representatives, form interactions with the S1′ and/or S2′ subsites of the enzyme, in addition to the S1 and S2 binding . Sitagliptin, gemigliptin, anagliptin, and teneligliptin, representatives of Class 3, interact with subsites S1 and S2, as well as with S2 extensive subsite of the enzyme . Interactions other than those with S1 and S2 subsites increase the potency of DPP‐4 inhibitors and allow selective targeting of DPP‐4 among related proteases by which drug side effects can be minimized.…”

Section: Dipeptidyl Peptidase‐4 and Its Clinically Used Inhibitorsmentioning

confidence: 99%

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

Tomovic

Lazarević

Kocić

et al. 2018

Medicinal Research Reviews

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Dipeptidyl peptidase-4 (DPP-4) cleaves N-terminal dipeptides, with Pro, Ala or Ser at the penultimate position, and, in that way, modulates biological activity of certain polypeptides. Due to its ubiquitous distribution, many pathological processes are associated with altered DPP-4 expression and activity. Besides the regulation of glucose metabolism, DPP-4 also exhibits many other systemic effects, and the inhibition of its activity might lead to cardiovascular and renal protection. Mechanisms underlying these protective effects of DPP-4 inhibition are ascribed to elevated bioavailability of its substrates, to impacts on mediators and signaling pathways that ameliorate cardiovascular and renal function through the suppression of oxidative stress, inflammation, fibrosis and apoptosis, improved endothelial function and tissue reparation. Inflammation contributes to and promotes progression of cardiovascular and renal disorders. Herein, we discuss cellular and molecular mechanisms mediating the anti-inflammatory activity of clinically used DPP-4 inhibitors in cardiovascular and renal protection.

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“…This binding mode of anagliptin leads to high and selective DPP-4 inhibition. Furthermore, anagliptin binds to Ser630 of DPP-4, which is a catalytic residue and a center of its activation in the S1 subsite, through a dipole interaction of the cyanopyrrolidine structure, and anagliptin may possibly lead to the formation of the imidate intermediates through covalent binding to DPP-4 34. Vildagliptin also binds to DPP-4 through covalent binding, which is thought to be a strong binding form 33.…”

Section: Discussionmentioning

confidence: 99%

Anagliptin ameliorates albuminuria and urinary liver-type fatty acid-binding protein excretion in patients with type 2 diabetes with nephropathy in a glucose-lowering-independent manner

Kitada

Tsuda

Konishi

et al. 2017

BMJ Open Diab Res Care

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ObjectiveThe objective of this study is to elucidate the effect of anagliptin on glucose/lipid metabolism and renoprotection in patients with type 2 diabetic nephropathy.MethodsTwenty-five patients with type 2 diabetic nephropathy received anagliptin 200 mg/day for 24 weeks, and 20 patients who were switched to anagliptin from other dipeptidyl peptidase-4 (DPP-4) inhibitors were analyzed regarding primary and secondary endpoints. The primary endpoint was change in hemoglobin A1c (HbA1c) during treatment with anagliptin. Additionally, we evaluated changes in lipid data (low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglyceride), blood pressure (BP), urinary albumin to creatinine ratio (UACR), liver-type fatty acid-binding protein to creatinine ratio (ULFABP) and renal function (estimated glomerular filtration rate and serum cystatin C) as secondary endpoints.ResultsAfter switching to anagliptin from other DPP-4 inhibitors, the levels of HbA1c in the 20 participants showed no significant change, 7.5%±1.2% at 24 weeks compared with 7.3%±0.9% at baseline. The levels of the log10-transformed UACR were significantly reduced from 1.95±0.51 mg/g creatinine (Cr) at baseline to 1.76±0.53 mg/g Cr at 24 weeks after anagliptin treatment (p<0.01). The percentage change in the UACR (Δ%UACR) from baseline to 24 weeks was also significantly lower by −10.6% (p<0.001). Lipid data, systolic BP and renal function were not changed during anagliptin treatment. Additionally, ULFABP in eight participants, who had ≥5 µg/g Cr at baseline, was significantly decreased from baseline (8.5±2.8 µg/g Cr) to 24 weeks (3.1±1.7 µg/g Cr, p<0.01) after anagliptin treatment, and the percentage change in the ULFABP during anagliptin treatment was −58.1% (p<0.001).ConclusionsAnagliptin induced no significant change in HbA1c, lipid data, systolic BP and renal function. However, anagliptin reduced the UACR and ULFABP, although without a corresponding change in HbA1c, indicating direct action of anagliptin on renoprotection in patients with type 2 diabetic nephropathy.

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Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions

Cited by 39 publications

References 32 publications

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

Anagliptin ameliorates albuminuria and urinary liver-type fatty acid-binding protein excretion in patients with type 2 diabetes with nephropathy in a glucose-lowering-independent manner

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