(2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]- pyridin-6-ylphenyl)butanamide:  A Selective α-Amino Amide Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

Edmondson, Scott D.; Mastracchio, Anthony; Mathvink, Robert J.; He, Jiafang; Harper, Bart; Park, You-Jung; Beconi, Maria; Salvo, Jerry Di; Eiermann, George J.; He, Huaibing; Leiting, Barbara; Leone, Joseph F.; Levorse, Dorothy; Lyons, Kathryn A.; Patel, Reshma A.; Patel, Sangita; Petrov, A. N.; Scapin, Giovanna; Shang, Jackie; Roy, Ranabir Sinha; Smith, Aaron; Wu, Joseph K.; Xu, Shiyao; Zhu, Bing; Thornberry, Nancy A.; Weber, Ann E.

doi:10.1021/jm060015t

Cited by 120 publications

(66 citation statements)

References 42 publications

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“…MK0626, a new DPP-4 inhibitor provided by Merck pharmaceuticals, was added to mouse chow so that the final concentration in chow was 33 mg MK0626•kg −1 chow to achieve a dose and plasma level of approximately 10 mg•kg −1 •day −1 and 100 nM, respectively. This dose was based on previous developmental studies of this DPP-4 inhibitor and clinical studies on the related FDA approved DPP-4 inhibitor, sitagliptin [33]. …”

Section: Methodsmentioning

confidence: 99%

Dipeptidyl peptidase inhibition prevents diastolic dysfunction and reduces myocardial fibrosis in a Mouse model of Western diet induced obesity

Bostick¹,

Habibi²,

Ma³

et al. 2014

Metabolism

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Objective Consumption of a high-fat/high-fructose Western diet (WD) is linked to rising obesity and heart disease, particularly diastolic dysfunction which characterizes early obesity/metabolic cardiomyopathy. Mounting evidence supports a role for inflammation, oxidative stress and fibrosis in the pathophysiology of metabolic cardiomyopathy. Dipeptidyl peptidase-4 (DPP-4) is a circulating exopeptidase recently reported to be elevated in the plasma of patients with insulin resistance (IR), obesity and heart failure. We hypothesized that a model of WD induced obesity/metabolic cardiomyopathy would exhibit increased DPP-4 activity and cardiac fibrosis with DPP-4 inhibition preventing cardiac fibrosis and the associated diastolic dysfunction. Materials/Methods Four-week-old C57BL6/J mice were fed a high-fat/high-fructose WD with the DPP-4 inhibitor MK0626 for 16 weeks. Cardiac function was examined by high-resolution cine-cardiac magnetic resonance imaging (MRI). Phenotypic analysis included measurements of body and heart weight, systemic IR and DPP-4 activity. Immunohistochemistry and transmission electron microscopy (TEM) were utilized to identify underlying pathologic mechanisms. Results We found that chronic WD consumption caused obesity, IR, elevated plasma DPP-4 activity, heart enlargement and diastolic dysfunction. DPP-4 inhibition with MK0626 in WD fed mice resulted in >75% reduction in plasma DPP-4 activity, improved IR and normalized diastolic relaxation. WD consumption induced myocardial oxidant stress and fibrosis with amelioration by MK0626. TEM of hearts from WD fed mice revealed abnormal mitochondrial and perivascular ultrastructure partially corrected by MK0626. Conclusions This study provides evidence of a role for increased DPP-4 activity in metabolic cardiomyopathy and a potential role for DPP-4 inhibition in prevention and/or correction of oxidant stress/fibrosis and associated diastolic dysfunction.

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Section: Methodsmentioning

confidence: 99%

Dipeptidyl peptidase inhibition prevents diastolic dysfunction and reduces myocardial fibrosis in a Mouse model of Western diet induced obesity

Bostick¹,

Habibi²,

Ma³

et al. 2014

Metabolism

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“…Here, we can see a ligand (S14 B1002 in PDB entry 2FJP [23]) and its binding site, from the analysis of DPP4_HUMAN using the Default (PDB) profile. The only dubious residue from the binding site is the one with the yellow ED represented as ball and stick and colored by B-factor.…”

Section: Methodsmentioning

confidence: 99%

The good, the bad and the dubious: VHELIBS, a validation helper for ligands and binding sites

et al. 2013

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BackgroundMany Protein Data Bank (PDB) users assume that the deposited structural models are of high quality but forget that these models are derived from the interpretation of experimental data. The accuracy of atom coordinates is not homogeneous between models or throughout the same model. To avoid basing a research project on a flawed model, we present a tool for assessing the quality of ligands and binding sites in crystallographic models from the PDB.ResultsThe Validation HElper for LIgands and Binding Sites (VHELIBS) is software that aims to ease the validation of binding site and ligand coordinates for non-crystallographers (i.e., users with little or no crystallography knowledge). Using a convenient graphical user interface, it allows one to check how ligand and binding site coordinates fit to the electron density map. VHELIBS can use models from either the PDB or the PDB_REDO databank of re-refined and re-built crystallographic models. The user can specify threshold values for a series of properties related to the fit of coordinates to electron density (Real Space R, Real Space Correlation Coefficient and average occupancy are used by default). VHELIBS will automatically classify residues and ligands as Good, Dubious or Bad based on the specified limits. The user is also able to visually check the quality of the fit of residues and ligands to the electron density map and reclassify them if needed.ConclusionsVHELIBS allows inexperienced users to examine the binding site and the ligand coordinates in relation to the experimental data. This is an important step to evaluate models for their fitness for drug discovery purposes such as structure-based pharmacophore development and protein-ligand docking experiments.

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“…Highly selective dipeptidyl peptidase IV (DPP IV) inhibitors are quite different from conventional antidiabetic agents and control hyperglycemia by stimulating insulin production via the prevention of the degradation of two major incretins, the glucagon-like peptide-1 (GLP-1) and the glucose inhibitory peptide (GIP) [5]–[7]. In addition, DPP IV inhibitors have protective effects against inflammation, oxidative injury, and apoptotic cell death in various disease models [8]–[12].…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase IV Inhibitor MK-0626 Attenuates Pancreatic Islet Injury in Tacrolimus-Induced Diabetic Rats

et al. 2014

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BackgroundTacrolimus (TAC)-induced pancreatic islet injury is one of the important causes of new-onset diabetes in transplant recipients. This study was performed to evaluate whether a dipeptidyl peptidase IV (DPP IV) inhibitor is effective in improving TAC-induced diabetes mellitus by reducing pancreatic islet injury.MethodsRats were treated with TAC (1.5 mg/kg, subcutaneously) and the DPP IV inhibitor MK-0626 (10 or 20 mg/kg, oral gavage) for 4 weeks. The effect of MK-0626 on TAC-induced diabetes was evaluated by assessing pancreatic islet function, histopathology. TAC-induced incretin dysfunction was also examined based on active glucagon-like peptide-1 (GLP-1) levels in the serum after glucose loading. The protective effect of MK-0626 was evaluated by measuring markers of oxidative stress, oxidative resistance, and apoptosis. To determine whether enhanced GLP-1 signaling is associated with these protective effects, we measured the expression of the GLP-1 receptor (GLP-1R) and the effect of the GLP-1 analog exendin-4 on cell viability and oxidative stress in isolated islets.ResultsMK-0626 treatment attenuated TAC-induced pancreatic islet dysfunction and islet morphology. TAC treatment led to a defect in active GLP-1 secretion; however, MK-0626 reversed these effects. TAC treatment increased the level of 8-hydroxy-2′-deoxyguanosine (8-OHdG), the number of apoptotic death, and the level of active caspase-3, and decreased the level of manganese superoxide dismutase and heme oxygenase-1; MK-0626 treatment reversed these changes. MK-0626 treatment restored the expression of GLP-1R, and direct administration of exendin-4 to isolated islets reduced TAC-induced cell death and 8-OHdG expression.ConclusionsThe DPP IV inhibitor MK-0626wasan effective antidiabetic agent that exerted antioxidative and antiapoptotic effects via enhanced GLP-1 signaling in TAC-induced diabetics.

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(2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]- pyridin-6-ylphenyl)butanamide: A Selective α-Amino Amide Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

Cited by 120 publications

References 42 publications

Dipeptidyl peptidase inhibition prevents diastolic dysfunction and reduces myocardial fibrosis in a Mouse model of Western diet induced obesity

Dipeptidyl peptidase inhibition prevents diastolic dysfunction and reduces myocardial fibrosis in a Mouse model of Western diet induced obesity

The good, the bad and the dubious: VHELIBS, a validation helper for ligands and binding sites

Dipeptidyl Peptidase IV Inhibitor MK-0626 Attenuates Pancreatic Islet Injury in Tacrolimus-Induced Diabetic Rats

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