Azetidine-Based Inhibitors of Dipeptidyl Peptidase IV (DPP IV)

Ferraris, Dana; Belyakov, S. A.; Li, Weixing; Oliver, Eddie; Ko, Yao Sen; Calvin, David; Lautar, Susan; Thomas, Bert E.; Rojas, Camilo

doi:10.2174/156802607780090993

Cited by 23 publications

(5 citation statements)

References 25 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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“…2‐Ketoazetidine derivative 6b was the most potent, with an IC 50 value of 0.042 μM, followed by 2‐cyanoazetidine, with an IC 50 value of 1.5 μM. [ 59 ]…”

Section: Therapeutic Importance Of Molecules Containing the Azetidine Heterocyclementioning

confidence: 99%

Azetidines of pharmacological interest

Parmar

Soni²,

Guduru

et al. 2021

Archiv der Pharmazie

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Azetidines are almost unexplored among nitrogen‐containing saturated heterocycles due to difficulties associated with their synthesis. However, over the past few years, attempts have been made by scientists to advance their synthetic feasibility. Compounds with the azetidine moiety display an important and diverse range of pharmacological activities, such as anticancer, antibacterial, antimicrobial, antischizophrenic, antimalarial, antiobesity, anti‐inflammatory, antidiabetic, antiviral, antioxidant, analgesic, and dopamine antagonist activities, and are also useful for the treatment of central nervous system disorders and so forth. Owing to its satisfactory stability, molecular rigidity, and chemical and biological properties, azetidine has emerged as a valuable scaffold and it has drawn the attention of medicinal researchers. The present review sheds light on the traditional method of synthesis of azetidine and advancements in synthetic methodology over the past few years, along with its application with various examples, and its biological significance.

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“…23 Sitagliptin (Januvia ® ) is the principle compound from this class and was the first FDA approved DDP-4 inhibitor. Xanthine-based 24 compounds are believed to have higher potency, longer-lasting inhibition, and longer-lasting improvement of glucose tolerance. Alogliptin (Nesina ® ) is the first drug in this class.…”

Section: Mechanism Of Action Of Dpp-4 Inhibitorsmentioning

confidence: 99%

Saxagliptin: A Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

Shubrook

Colucci

Guo

et al. 2011

Clin Med Insights Endocrinol Diabetes

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The prevalence of type 2 diabetes mellitus is high and growing rapidly. Suboptimal glycemic control provides opportunities for new treatment options to improve the morbidity and mortality of this progressive disease. Saxagliptin, a selective DPP-4 inhibitor, increases endogenous incretin levels and incretin acitivty. In controlled clinical trials saxagliptin reduces both fasting and postprandial glucose and works in monotherapy and in combination with metformin, TZDs and sulfonylureas. Saxagliptin has a very favourable side effect profile and may have other beneficial non-glycemic effects. The authors review the current available evidence for the safety, efficacy and saxagliptin’s place in therapy for type 2 diabetes mellitus. As understanding of the incretin hormones (GLP-1, GIP) expand we may see additional important non-glycemic effects that may affect the chronic management of type 2 diabetes mellitus.

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Azetidine-Based Inhibitors of Dipeptidyl Peptidase IV (DPP IV)

Cited by 23 publications

References 25 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

Azetidines of pharmacological interest

Saxagliptin: A Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

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