(<i>R</i>)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a Novel Xanthine-Based Dipeptidyl Peptidase 4 Inhibitor, Has a Superior Potency and Longer Duration of Action Compared with Other Dipeptidyl Peptidase-4 Inhibitors

Thomas, Leo H.; Eckhardt, Matthias; Langkopf, Elke; Tadayyon, Moh; Himmelsbach, Frank; Michael, Mark

doi:10.1124/jpet.107.135723

Cited by 266 publications

(243 citation statements)

References 30 publications

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“…Saxagliptin may also enhance eNOS function by reducing postprandial glucose and increasing levels of GLP-1, an incretin hormone that increases endothelial-dependent NO release, independent of changes in glucose levels 17,18) . Saxagliptin treatment has also been shown to increase levels of GLP-1 in obese Zucker rats 19) . Other important substrates for DPP4 may be involved in this process, including brain natriuretic peptide (BNP), a 32-amino acid hormone that has vasodilating and natriuretic properties 20) .…”

Section: Discussionmentioning

confidence: 99%

Effect of Enhanced Glycemic Control with Saxagliptin on Endothelial Nitric Oxide Release and CD40 Levels in Obese Rats

Mason

Jacob²,

Kubant

et al. 2011

JAT

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Aim: Endothelial cell (EC) dysfunction contributes to insulin resistance in diabetes and is characterized by reduced nitric oxide (NO) release, increased nitroxidative stress and enhanced inflammation. The purpose of this study was to test the effect of improved postprandial glucose control on EC function in insulin-resistant rats as compared to fasting glucose (FG) changes. Methods: Obese Zucker rats were treated with 10 mg/kg/day saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, for 4 or 8 weeks and compared to lean rats. NO and peroxynitrite (ONOO ) release from aortic and glomerular ECs was measured ex vivo using amperometric approaches and correlated with FG, postprandial glucose, insulin, soluble CD40 (sCD40) and L-citrulline levels. Results: Saxagliptin treatment improved NO production and reduced ONOO release prior to any observed changes in FG levels. In untreated obese animals, NO release from aortic and glomerular ECs decreased by 22% and 31%, respectively, while ONOO release increased by 26% and 40%. Saxagliptin increased aortic and glomerular NO release by 18% and 31%, respectively, with comparable reductions in ONOO levels; the NO/ONOO ratio, an indicator of NO synthase coupling, increased by 40%. Improved glycemic control was further associated with a reduction in sCD40 levels by more than ten-fold (from 300 206 to 22 22 pg/mL, p 0.001). Conclusion: These findings indicate that enhanced glycemic control with DPP4 inhibition improved NO release and reduced inflammation in a manner not predicted by FG changes alone. J Atheroscler Thromb, 2011; 18:774-783.

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Section: Discussionmentioning

confidence: 99%

Effect of Enhanced Glycemic Control with Saxagliptin on Endothelial Nitric Oxide Release and CD40 Levels in Obese Rats

Mason

Jacob²,

Kubant

et al. 2011

JAT

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“…Linagliptin is a potent and selective DPP-4 inhibitor (4). In a phase III study in patients with type 2 diabetes (5), linagliptin 5 mg given as an add-on to metformin treatment for 24 weeks improved glycemic control without weight gain and was well tolerated, with a low risk of hypoglycemia.…”

mentioning

confidence: 99%

Empagliflozin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, Double-Blind, Parallel-Group Trial

et al. 2016

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OBJECTIVETo evaluate the efficacy and safety of empagliflozin versus placebo as add-on therapy in patients with type 2 diabetes and inadequate glycemic control with linagliptin and metformin. RESEARCH DESIGN AND METHODSPatients with HbA 1c ‡8.0% and £10.5% ( ‡64 and £91 mmol/mol) while receiving stable-dose metformin received open-label linagliptin 5 mg (n = 606) for 16 weeks. Subsequently, those with HbA 1c ‡7.0 and £10.5% ( ‡53 and £91 mmol/mol) were randomized to receive double-blind, double-dummy treatment with empagliflozin 10 mg (n = 112), empagliflozin 25 mg (n = 111), or placebo (n = 110) for 24 weeks; all patients continued treatment with metformin and linagliptin 5 mg. The primary end point was the change from baseline in HbA 1c after 24 weeks of double-blind treatment. RESULTSAt week 24, empagliflozin significantly reduced HbA 1c (mean baseline 7.96-7.97% [63-64 mmol/mol]) versus placebo; the adjusted mean differences in the change from baseline with empagliflozin 10 and 25 mg versus placebo were 20.79% (95% CI -1.02, -0.55) (28.63 mmol/mol [-11.20, -6.07 mmol/mol]) and 20.70% (95% CI -0.93, -0.46) (27.61 mmol/mol [-10.18, -5.05 mmol/mol]), respectively (both P < 0.001). Fasting plasma glucose and weight were significantly reduced in both empagliflozin groups versus placebo (P < 0.001 for all comparisons). More patients receiving placebo than empagliflozin 10 and 25 mg reported adverse events during double-blind treatment (68.2%, 55.4%, and 51.8%, respectively). CONCLUSIONSEmpagliflozin treatment for 24 weeks improved glycemic control and weight versus placebo as an add-on to linagliptin 5 mg and metformin and was well tolerated.

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“…The initial reaction rates of DPP-4 with different concentrations of extracts were analyzed using one-phase exponential decay equation and data indicates that the selected extracts inhibit DPP-4 in competition to substrate binding sites. Inhibitors that bind tightly to the target are important for the pharmacological activity, as they inhibit enzyme function even if the circulatory free drug is cleared (Thomas et al, 2008). K off and EI half-lives of PM, EJ and GS were found to be 1.49, 2.18 and 4.50 Â 10 À3 /s and, 462.3, 317.2 and 153.8 min, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Discovery of incretin hormone, glucagon-like peptide-1 (GLP-1) lead a breakthrough in diabetes research by regulating postprandial glucose levels. The risk of hypoglycemia will be minimized due to insulinotropic actions of GLP-1 (Thomas et al, 2008). Other than insulin secretion, GLP-1 is also responsible for beta cell regeneration with reduced apoptosis (Drucker, 2003).…”

Section: Introductionmentioning

confidence: 99%

A molecular connection ofPterocarpus marsupium, Eugenia jambolanaandGymnema sylvestrewith dipeptidyl peptidase-4 in the treatment of diabetes

Kosaraju¹,

Dubala²,

Chinni

et al. 2013

Pharmaceutical Biology

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Context: Pterocarpus marsupium (PM) (Leguminosae), Eugenia jambolana (EJ) (Myrtaceae) and Gymnema sylvestre (GS) (Asclepiadaceae) are the most important medicinal plants in the Indian system of traditional medicine for the treatment of hyperglycemia. Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are the emerging class of anti-diabetic agents. However, only few compounds are commercially available. Therefore, in the present study we tried to explore the naturally occurring PM, EJ and GS semi-standardized extracts for their potential DPP-4 inhibition in vitro and in vivo. Materials and methods: DPP-4 inhibition was evaluated by in vitro inhibitory assay, and enzyme kinetics were calculated using one-phase exponential decay equation. Glucose load (2 g/kg) was administered to control and diabetic rats 30 min following extract administration (100, 200 and 400 mg/kg) orally once, and blood samples were withdrawn at 0, 0.5, 1, 1.5, 2 and 3 h to measure plasma active glucagon-like peptide-1 (GLP-1) levels. Results: PM and EJ inhibit DPP-4 potently with IC 50 values of 273.73 AE 2.96 and 278.94 AE 6.73 mg/ mL, respectively, compared to GS (773.22 AE 9.21 mg/mL). PM, EJ and GS exhibit long duration of action with enzyme inhibitory half-lives of 462.3, 317.2 and 153.8 min, respectively. Extracts significantly increase GLP-1 levels compared to negative control groups and peak GLP-1 level was observed at 2 h for PM and EJ, whereas for GS it was at 1.5 h Discussion and conclusion: Taken together, results suggest the extracts may have potent DPP-4 inhibitory action, and their hypoglycemic action attributed through an increase in plasma active GLP-1 levels.

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(R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a Novel Xanthine-Based Dipeptidyl Peptidase 4 Inhibitor, Has a Superior Potency and Longer Duration of Action Compared with Other Dipeptidyl Peptidase-4 Inhibitors

Cited by 266 publications

References 30 publications

Effect of Enhanced Glycemic Control with Saxagliptin on Endothelial Nitric Oxide Release and CD40 Levels in Obese Rats

Effect of Enhanced Glycemic Control with Saxagliptin on Endothelial Nitric Oxide Release and CD40 Levels in Obese Rats

Empagliflozin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, Double-Blind, Parallel-Group Trial

A molecular connection ofPterocarpus marsupium, Eugenia jambolanaandGymnema sylvestrewith dipeptidyl peptidase-4 in the treatment of diabetes

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