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A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes. As the resul...
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A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes. As the results of structure-activity relationship (SAR) study of the series, the compounds with 4-methylquinazoline- 2-yl-methyl group at N-1 position and 2-aminoethylaminomethyl group gave better activities. Compounds H4 and H9 showed good DPP-4 inhibition and more than 100-fold selectivity over DPP-7 and DPP-8.
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The proline-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD_26), widely expressed in mammalians, releases X-Pro/Ala dipeptides from the N-terminus of peptides. DPP IV is responsible of the degradation of the incretin pept...
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The proline-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD_26), widely expressed in mammalians, releases X-Pro/Ala dipeptides from the N-terminus of peptides. DPP IV is responsible of the degradation of the incretin peptide hormones regulating blood glucose levels. Several families of DPP IV inhibitors have been synthesized and evaluated. Their positive effects on the degradation of the incretins and the control of blood glucose levels have been demonstrated in biological models and in clinical trials. Presently, several DPP IV inhibitors, the "gliptins", are approved for type 2 diabetes or are under clinical evaluation. However, the gliptins may also be of therapeutic interest for other diseases beyond the inhibition of incretin degradation. In this Perspective, the biological functions and potential substrates of DPP IV enzymes are reviewed and the characteristics of the DPP IV inhibitors are discussed in view of type 2 diabetes and further therapeutic interest.
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Abstract The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P.?gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biof...
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Abstract The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P.?gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P.?gingivalis DPP4 was solved at 2.2?? resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P.?gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates. Graphical abstract Display Omitted Highlights ? The crystal structure of Porphyromonas gingivalis DPP4 has been solved at 2.2?? resolution. ? Substrate binding sites are conserved between pgDPP4 and mammalian DPP4s. ? The S2-extended binding site is larger in pgDPP4 than in mammalian DPP4s. ? Clinically used DPP4 inhibitors do not inhibit pgDPP4. ? SAR of pgDPP4 inhibitors partly mimic that of DPP9.
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Dipeptidyl peptidase IV (DPP4) is a ubiquitous protease that can be found in membrane-anchored or soluble form. Incretins are one of the main DPP4 substrates. These hormones regulate glucose levels, by stimulating insulin secretio...
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Dipeptidyl peptidase IV (DPP4) is a ubiquitous protease that can be found in membrane-anchored or soluble form. Incretins are one of the main DPP4 substrates. These hormones regulate glucose levels, by stimulating insulin secretion and decreasing glucagon production. Because DPP4 levels are high in diabetes, DPP4 inhibitor (DPP4i) drugs derived from gliptin are widespread used as hypoglycemic agents for its treatment. However, as DPP4 recognizes other substrates such as chemokines, growth factors and neuropeptides, pleiotropic effects have been observed in patients treated with DPP4i. Several of these substrates are part of the stem-cell niche. Thus, they may affect different physiological aspects of mesenchymal stem-cells (MSC). They include viability, differentiation, mobilization and immune response. MSC are involved in tissue homeostasis and regeneration under both physiological and pathological conditions. Therefore, such cells and their secretomes have a high clinical potential in regenerative medicine. In this context, DPP4 activity may modulate different aspects of MSC regenerative capacity. Therefore, the aim of this review is to analyze the effect of different DPP4 substrates on MSC. Likewise, how the regulation of DPP4 activity by DPP4i can be applied in regenerative medicine. That includes treatment of cardiovascular and bone pathologies, cutaneous ulcers, organ transplantation and pancreatic beta-cell regeneration, among others. Thus, DPP4i has an important clinical potential as a complement to therapeutic strategies in regenerative medicine. They involve enhancing the differentiation, immunomodulation and mobilization capacity of MSC for regenerative purposes.
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Purpose: The effects of two types of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal function remain unclear. Thus, we investigated the effect of anagliptin (ANA) and sitagliptin (SITA) on renal function in patients with type 2...
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Purpose: The effects of two types of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal function remain unclear. Thus, we investigated the effect of anagliptin (ANA) and sitagliptin (SITA) on renal function in patients with type 2 diabetes who participated in the randomized evaluation of ANA versus SITA on low-density lipoprotein-cholesterol (LDL-C) in diabetes (REASON) trial.Patients and methods: We measured the estimated glomerular filtration rate (eGFR) and urinary albumin–creatinine ratio (UACR) before and after the REASON trial. ANA 200 mg/day was administered to 177 patients for 52 weeks, while SITA 50 mg/day was given to 176 patients. We investigated the relationship between differences in renal function and differences in hemoglobin A1c (HbA1c) levels, LDL-C levels, and blood pressure (BP).Results: No significant differences were found in baseline eGFR and UACR between the two groups. The eGFR levels were significantly decreased in both groups; however, the UACR level was unchanged in the ANA group but elevated in the SITA group, although the difference did not reach significance between the two groups. The difference in eGFR was affected by the differences in HbA1c level and BP, and the difference in the UACR was affected by the differences in LDL-C level and BP, which were reduced only in the ANA group.Conclusion: These findings imply that the effects of DPP-4 inhibitors on renal function, especially on UACR, may be different between the types of DPP-4 inhibitors.
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Aim: To assess the 54-week efficacy of initial combination therapy with sitagliptin and pioglitazone, compared with pioglitazone monotherapy, and to assess safety in these groups during the 30 weeks after the dosage of pioglitazon...
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Aim: To assess the 54-week efficacy of initial combination therapy with sitagliptin and pioglitazone, compared with pioglitazone monotherapy, and to assess safety in these groups during the 30 weeks after the dosage of pioglitazone was increased from 30 to 45 mg/day, in drug-na?ve patients with type 2 diabetes mellitus and inadequate glycaemic control [haemoglobin A1c (HbA1c) 8-12%]. Methods: Following a 24-week, randomized, double-blind, parallel-group study (Sitagliptin Protocol 064, Clinicaltrials.gov: NCT00397631; Yoon KH, Shockey GR, Teng R et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycaemic control and measures of beta-cell function in patients with type 2 diabetes. Int J Clin Pract 2011; 65: 154-164) in which patients were treated with the combination of sitagliptin 100 mg/day and pioglitazone 30 mg/day or monotherapy with pioglitazone 30 mg/day, patients entered a 30-week extension study. In the extension study, the pioglitazone dose was increased from 30 to 45 mg/day in both groups. Depending upon treatment allocation, patients took one tablet of sitagliptin 100 mg or matching placebo daily. Pioglitazone was administered in an open-label fashion as a single 45-mg tablet taken once daily. Patients not meeting specific glycaemic goals in the extension study were rescued with metformin therapy. Efficacy and safety results for the extension study excluded data after initiation of rescue therapy. Results: Of the 520 patients initially randomized, 446 completed the base study and, of these, 317 entered the extension. In this extension study cohort, the mean reductions from baseline in HbA1c and fasting plasma glucose (FPG) at the end of the base study (week 24) were -2.5% and -62.1 mg/dl with the combination of sitagliptin 100 mg and pioglitazone 30 mg versus -1.9% and -48.7 mg/dl with pioglitazone monotherapy. At the end of the extension study (week 54), the mean reduction in haemoglobin A1c (HbA1c) was -2.4% with the combination of sitagliptin 100 mg and pioglitazone 45 mg versus -1.9% with pioglitazone monotherapy [between-group difference (95% CI) = -0.5% (-0.8, -0.3)] and the mean reduction in FPG was -61.3 mg/dl versus -52.8 mg/dl, respectively [between-group difference (95% CI) = -8.5 mg/dl (-16.3, -0.7)]. Safety and tolerability of initial treatment with the combination of sitagliptin and pioglitazone and pioglitazone monotherapy were similar. As expected, increases in body weight from baseline were observed in both treatment groups at week 54: 4.8 and 4.1 kg in the combination and monotherapy groups, respectively [between-group difference (95% CI) = 0.7 kg (-0.7, 2.1)]. Conclusion: In this study, initial combination therapy with sitagliptin 100 mg and pioglitazone 30 mg increased to 45 mg after 24 weeks led to a substantial and durable incremental improvement in glycaemic control compared with initial treatment with pioglitazone monotherapy during a 54-week treatment period. Both initial combination therapy with sitagliptin and pioglitazone and pioglitazone monotherapy were generally well tolerated (Clinicaltrials.gov: NCT01028391).
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Numerous patients develop diabetes in response to glucocorticoid therapy. This study explored the efficacy, safety, and preventive potential of the dipeptidyl peptidase-4 inhibitor, linagliptin (TRADJENTA?), in the development of ...
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Numerous patients develop diabetes in response to glucocorticoid therapy. This study explored the efficacy, safety, and preventive potential of the dipeptidyl peptidase-4 inhibitor, linagliptin (TRADJENTA?), in the development of glucocorticoid-induced diabetes mellitus. From December 2014 to November 2015, we recruited non-diabetic Japanese patients scheduled for treatment with daily prednisolone ≥20?mg. Enrolled patients had at least one of following risk factors for glucocorticoid-induced diabetes mellitus: estimated glomerular filtration rate?≤?60?mL/minute/1.73?m 2 ; age?≥?65?years; hemoglobin A1c?>?6.0%. A daily dose of 5?mg of linagliptin was administered simultaneously with glucocorticoid therapy. The primary outcome was the development of glucocorticoid-induced diabetes mellitus. Additional orally administered hypoglycemic medications and/or insulin injection therapy was initiated according to the blood glucose level. Four of five patients developed glucocorticoid-induced diabetes mellitus within 1 week of glucocorticoid treatment. For 12?weeks, two of the four patients with glucocorticoid-induced diabetes mellitus required orally administered medications, but no patients required insulin. Blood glucose levels before breakfast and lunch tended to decrease with time; the median glucose levels before breakfast were 93 and 79.5?mg/dL at 1 and 3 weeks, respectively. Two patients experienced mild hypoglycemia around 2 weeks. Glucose levels after lunch remained high throughout all 4?weeks despite decreasing the glucocorticoid dosage. Linagliptin may be insufficient to prevent the development of glucocorticoid-induced diabetes mellitus but has the potential to reduce the requirement for insulin injection therapy. Treatment of glucocorticoid-induced diabetes mellitus was continued for at least 1 month and fasting hypoglycemia in early morning should be monitored after 2 weeks. This trial was registered 02 November 2014 with UMIN Clinical Trials Registry (no. 000015588 ).
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Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent the degradation of glucagon-like peptide-1 (GLP-1) and improve glycemic control. The GLP-1 insulinotropic effect involves a pathway through vagus nerve GLP-1 receptors in the gut, ...
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Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent the degradation of glucagon-like peptide-1 (GLP-1) and improve glycemic control. The GLP-1 insulinotropic effect involves a pathway through vagus nerve GLP-1 receptors in the gut, in addition to a direct effect on the pancreas. Therefore, this study verified whether DPP-4 inhibition in the gut contributed to the improvement of glycemic control. Anagliptin, a DPP-4 inhibitor, was administered orally or subcutaneously (with or without passing through the gastrointestinal tract, respectively) to mice. The association between blood glucose suppression following oral glucose challenge and DPP-4 inhibition in the small intestine and plasma was assessed. Oral administration of anagliptin (0.03-0.3 mg/kg) in normal mice significantly suppressed blood glucose, which was associated with an increase in insulin secretion at a dose of >= 0.1 mg/kg (P < 0.05). Subcutaneous administration of anagliptin (0.01-0.1 mg/kg) produced similar results. However, plasma DPP-4 inhibition following oral administration was weaker than that following subcutaneous administration; blood glucose suppression was significantly correlated with small intestinal DPP-4 inhibition (r = 0.949, P < 0.01), but not with plasma DPP-4 inhibition. Additionally, similar results were observed in a type 2 diabetes model (r = 0.975, P < 0.001). Thus, these results demonstrated that an improvement in glycemic control was dependent upon small intestinal DPP-4 inhibition. As these effects were accompanied by the elevation of intact GLP-1 in the portal, this suggests that improvement in glucose tolerance after anagliptin treatment might be related to an increase in GLP-1 receptor signaling in the small intestine and portal vein.
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