Novel 5‐(1‐aryl‐1 H ‐pyrazol‐3‐yl)‐1 H ‐tetrazoles as glycogen phosphorylase inhibitors: An in vivo antihyperglycemic activity study

2019 ◽  
Vol 81 (1) ◽  
pp. 70-84
Author(s):  
Pramod P. Kattimani ◽  
Shilpa M. Somagond ◽  
Praveen K. Bayannavar ◽  
Ravindra R. Kamble ◽  
Subhas C. Bijjaragi ◽  
...  
Keyword(s):  
Glycogen Phosphorylase ◽  
Antihyperglycemic Activity ◽  
Glycogen Phosphorylase Inhibitors

Discovery and evaluation of novel benzazepinone derivatives as glycogen phosphorylase inhibitors with potent activity

2021 ◽  
pp. 00-00
Author(s):  
Youde Wang ◽  
Zhiwei Yan ◽  
Yachun Guo ◽  
Liying Zhang
Keyword(s):  
Glycogen Phosphorylase ◽  
Fasting Blood Glucose ◽  
Binding Mode ◽  
Rabbit Muscle ◽  
Fasting Blood Glucose Level ◽  
Docking Simulations ◽  
Key Enzyme ◽  
Glycogen Phosphorylase Inhibitors ◽  
Glycogen Catabolism

Glycogen phosphorylase (GP) is a key enzyme of glycogen catabolism, so it is significant to discover a new GP inhibitor. A series of benzazepinone derivatives were discovered as GP inhibitors with potent activity. Among these derivatives, compound 5d showed significant potential against rabbit muscle GPa (IC50 = 0.25 ± 0.05 μM) and cellular efficacy. The in vivo study revealed that 5d significantly inhibited increases in fasting blood glucose level in two kinds of hyperglycemic mice models. The possible binding mode of compound 5d was explored based on molecular docking simulations. These results indicated that derivatives with benzazepinone were potential chemical entities against hyperglycemia.

Endogenous effectors of human liver glycogen phosphorylase modulate effects of indole-site inhibitors

2005 ◽  
Vol 289 (3) ◽  
pp. E366-E372 ◽  
Author(s):  
Nacide Ercan-Fang ◽  
Miriam R. Taylor ◽  
Judith L. Treadway ◽  
Carolyn B. Levy ◽  
Paul E. Genereux ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Human Liver ◽  
Glycogen Phosphorylase ◽  
Liver Glycogen ◽  
Inhibitory Effect ◽  
Small Molecular Weight ◽  
Glucose Lowering ◽  
Glycogen Phosphorylase Inhibitors

Phosphorylase is regulated by a number of small-molecular-weight effectors that bind to three sites on the enzyme. Recently, a fourth site referred to as the indole-inhibitor site has been identified. Synthetic compounds bind to the site and inhibit activity. However, the effects of these compounds in the presence of other endogenous effectors are unknown. We have determined the effects of four indole derivative glycogen phosphorylase inhibitors (GPI) on recombinant human liver glycogen phosphorylase a activity. The GPIs tested were all potent inhibitors. However, the endogenous inhibitors (glucose, ADP, ATP, fructose 1-phosphate, glucose 6-phosphate, UDP-glucose) and the activator (AMP) markedly reduced the inhibitory effect of GPIs. Consistent with these in vitro findings, the IC50 for the inhibition of glycogenolysis in cells and the liver drug concentration associated with glucose-lowering activity in diabetic ob/ ob mice in vivo were also significantly higher than those determined in in vitro enzyme assays. The inhibitory effect of indole-site effectors is modulated by endogenous small-molecular-weight effectors of phosphorylase a activity. However, at higher concentrations (10–30 μM), the GPI effect was dominant and resulted in inhibition of phosphorylase a activity irrespective of the presence or absence of the other modulators of the enzyme.

Phytogenic Polyphenols as Glycogen Phosphorylase Inhibitors: The Potential of Triterpenes and Flavonoids for Glycaemic Control in Type 2 Diabetes

2017 ◽  
Vol 24 (4) ◽  
pp. 384-403 ◽  
Author(s):  
Demetres Leonidas ◽  
Joseph Hayes ◽  
Atsushi Kato ◽  
Vassiliki Skamnaki ◽  
Demetra Chatzileontiadou ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glycaemic Control ◽  
Glycogen Phosphorylase ◽  
Glycogen Phosphorylase Inhibitors

Glycogen phosphorylase in fish muscle: demonstration of three interconvertible forms

1990 ◽  
Vol 258 (2) ◽  
pp. C344-C351 ◽  
Author(s):  
H. Schmidt ◽  
G. Wegener
Keyword(s):  
Glycogen Phosphorylase ◽  
Specific Activity ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Muscular Activity ◽  
Fish Muscle ◽  
Kinetic Properties ◽  
Phosphorylase Activity ◽  
Tissue Extracts

White skeletal muscle of crucian carp contains a single isoenzyme of glycogen phosphorylase, which was purified approximately 300-fold to a specific activity of approximately 13 mumol.min-1.mg protein-1 (assayed in the direction of glycogen breakdown at 25 degrees C). Tissue extracts of crucian muscle produced three distinct peaks of phosphorylase activity when separated on DEAE-Sephacel. Peaks 1 and 3 were identified, in terms of kinetic properties and by interconversion experiments, as phosphorylase b and a, respectively. Peak 2 was shown to be a phospho-dephospho hybrid. The three interconvertible forms of phosphorylase were purified and shown to be dimeric molecules at 20 degrees C. At 5 degrees C, a and the hybrid tended to form tetramers. The Mr of the subunit was estimated to be 96,400 from sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The hybrid is kinetically homogeneous, and its kinetic properties are intermediate between those of b and a forms. The b, hybrid, and a forms of phosphorylase can be isolated from rapidly frozen muscle of crucian but in different proportions, depending on whether fish were anesthetized or forced to muscular activity for 20 s. Muscle of anesthetized crucian had 36, 36, and 28% of phosphorylase b, hybrid, and a forms, respectively, whereas the corresponding values for exercised fish were 12, 37, and 51%. Results suggest that three interconvertible forms of phosphorylase exist simultaneously in crucian muscle and that hybrid phosphorylase is active in contracting muscle in vivo.

scholarly journals Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs

2005 ◽  
Vol 14 (7) ◽  
pp. 1760-1771 ◽  
Author(s):  
Nikos G. Oikonomakos ◽  
Magda N. Kosmopoulou ◽  
Evangelia D. Chrysina ◽  
Demetres D. Leonidas ◽  
Ioannis D. Kostas ◽  
...  
Keyword(s):  
Glycogen Phosphorylase ◽  
Antidiabetic Drugs ◽  
New Class ◽  
Glycogen Phosphorylase Inhibitors

Glycogen phosphorylase inhibitors: a patent review (2008 – 2012)

2013 ◽  
Vol 23 (8) ◽  
pp. 1017-1032 ◽  
Author(s):  
Nicolas Gaboriaud-Kolar ◽  
Alexios-Leandros Skaltsounis
Keyword(s):  
Glycogen Phosphorylase ◽  
Patent Review ◽  
Glycogen Phosphorylase Inhibitors
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