Synthesis, biological evaluation and structural determination of β-aminoacyl-containing cyclic hydrazine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors

Ahn, Jin Hee; Shin, Mi Sik; Jun, Mi Ae; Jung, Sun Ho; Kang, Seung Kyu; Kim, Kwang-Rok; Rhee, Sang Dal; Kang, Nam Sook; Kim, Sun Young; Sohn, Sang-Kwon; Kim, Sung Gyu; Jin, Mi Sun; Lee, Jie‐Oh; Cheon, Hyae Gyeong; Kim, Sung Soo

doi:10.1016/j.bmcl.2007.01.111

Cited by 47 publications

(14 citation statements)

References 27 publications

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“…Incretin hormones have potent insulin-secretory activity and are as such antidiabetic. As DPP-IV inactivates GLP-1 and GIP, inhibitors of DPP-IV have been found useful in the treatment of type 2 diabetes and other diseases (54,(57)(58)(59)(60)(61)(62)(63).…”

Section: Resultsmentioning

confidence: 99%

Characterization of Human Myotubes From Type 2 Diabetic and Nondiabetic Subjects Using Complementary Quantitative Mass Spectrometric Methods

Thingholm

Bak

Beck‐Nielsen

et al. 2011

Molecular & Cellular Proteomics

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Skeletal muscle is a key tissue site of insulin resistance in type 2 diabetes. Human myotubes are primary skeletal muscle cells displaying both morphological and biochemical characteristics of mature skeletal muscle and the diabetic phenotype is conserved in myotubes derived from subjects with type 2 diabetes. Several abnormalities have been identified in skeletal muscle from type 2 diabetic subjects, however, the exact molecular mechanisms leading to the diabetic phenotype has still not been found. Here we present a large-scale study in which we combine a quantitative proteomic discovery strategy using isobaric peptide tags for relative and absolute quantification (iTRAQ) and a label-free study with a targeted quantitative proteomic approach using selected reaction monitoring to identify, quantify, and validate changes in protein abundance among human myotubes obtained from nondiabetic lean, nondiabetic obese, and type 2 diabetic subjects, respectively. Using an optimized protein precipitation protocol, a total of 2832 unique proteins were identified and quantified using the iTRAQ strategy.Despite a clear diabetic phenotype in diabetic myotubes, the majority of the proteins identified in this study did not exhibit significant abundance changes across the patient groups. Proteins from all major pathways known to be important in type 2 diabetic subjects were wellcharacterized in this study. This included pathways like the trichloroacetic acid (TCA) cycle, lipid oxidation, oxidative phosphorylation, the glycolytic pathway, and glycogen metabolism from which all but two enzymes were found in the present study. None of these enzymes were found to be regulated at the level of protein expression or degradation supporting the hypothesis that these pathways are regulated at the level of post-translational modification. Twelve proteins were, however, differentially expressed among the three different groups. Thirty-six proteins were chosen for further analysis and validation using selected reaction monitoring based on the regulation identified in the iTRAQ discovery study. The abundance of adenosine deaminase was considerably downregulated in diabetic myotubes and as the protein binds propyl dipeptidase (DPP-IV), we speculate whether the reduced binding of adenosine deaminase to DPP-IV may contribute to the diabetic phenotype in vivo by leading to a higher level of free DPP-IV to bind and inactivate the anti-diabetic hormones, glucagon-like peptide-1 and glu-

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Section: Resultsmentioning

confidence: 99%

Characterization of Human Myotubes From Type 2 Diabetic and Nondiabetic Subjects Using Complementary Quantitative Mass Spectrometric Methods

Thingholm

Bak

Beck‐Nielsen

et al. 2011

Molecular & Cellular Proteomics

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“…It is now believed that molecules capable of inserting into the hydrophobic grove of MD-2, preventing LPS to insert, have antagonist activity. This has been well described for lipid IVa (21), Eritoran, a lipid IVa analog also containing four acyl chains (22), as well as curcuma (23,24). Other triacylated compounds have TLR4/MD-2 antagonistic activities, most likely by inserting into the hydrophobic pocket of MD-2, such as CRX-527, an aminoalkyl glucosaminide 4-phosphate (25).…”

Section: Discussionmentioning

confidence: 80%

Toll-like Receptor Activation of Human Cells by Synthetic Triacylated Lipid A-like Molecules

Dunn-Siegrist

Tissières

Drifte

et al. 2012

Journal of Biological Chemistry

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Background: Binding of LPSs and lipopeptides to Toll-like receptors depends on their lipid moieties. Results: Synthetic triacylated LPS-like molecules bind to TLR2 (weak agonists) and TLR4 (strong antagonists) and block phagocytosis of Gram-negative bacteria. Conclusion: Triacylated LPS-like molecules are potent TLR4 antagonists. Significance: These compounds may represent valuable LPS antagonists and immunomodulators.

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“…Substrate-like DPP-4 inhibitors usually have an electrophilic group that can interact either covalently or noncovalently with the active binding site of the enzyme [18]. Cyanopyrrolidines are competitive inhibitors of the DPP-4 enzyme and form reversible covalent bonds with the catalytically active serine hydroxyl (Ser630) site [19,20].…”

Section: Chemistry Of Dpp-4 Inhibitorsmentioning

confidence: 99%

“…GLP-1 stimulates insulin biosynthesis and secretion by the beta cells, inhibits glucagon secretion, slows gastric emptying, reduces appetite and stimulates regeneration of islet b-cells [16]. GIP and GLP-1 have extremely short plasma halflifes owing to a very rapid inactivation by the enzyme DPP-4, which selectively cleaves two amino acids from GLP-1 and GIP that are crucial for biological activity [18,19]. The DPP-4 enzyme is attached to the plasma membrane of the endothelia of almost all organs, tissues and fluids of the body.…”

Section: Introduction To the Dpp-4 Inhibitorsmentioning

confidence: 99%

Exploration of the DPP-4 inhibitors with a focus on saxagliptin

Shubrook

Colucci

Schwartz³

2009

Expert Opinion on Pharmacotherapy

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Synthesis, biological evaluation and structural determination of β-aminoacyl-containing cyclic hydrazine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors

Cited by 47 publications

References 27 publications

Characterization of Human Myotubes From Type 2 Diabetic and Nondiabetic Subjects Using Complementary Quantitative Mass Spectrometric Methods

Characterization of Human Myotubes From Type 2 Diabetic and Nondiabetic Subjects Using Complementary Quantitative Mass Spectrometric Methods

Toll-like Receptor Activation of Human Cells by Synthetic Triacylated Lipid A-like Molecules

Exploration of the DPP-4 inhibitors with a focus on saxagliptin

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