Synthesis, in vitro ADME profiling and in vivo pharmacological evaluation of novel glycogen phosphorylase inhibitors

2020 ◽  
Vol 30 (14) ◽  
pp. 127117
Author(s):  
Guang-xin Miao ◽  
You-de Wang ◽  
Zhi-wei Yan ◽  
Li-ying Zhang
Keyword(s):  
Glycogen Phosphorylase ◽  
Pharmacological Evaluation ◽  
Glycogen Phosphorylase Inhibitors

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.

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.

scholarly journals In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018

2020 ◽  
Vol 193 ◽  
pp. 172918
Author(s):  
Thomas F. Gamage ◽  
Daniel G. Barrus ◽  
Richard C. Kevin ◽  
David B. Finlay ◽  
Timothy W. Lefever ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Pharmacological Evaluation ◽  
Synthetic Cannabinoid Receptor Agonist

Synthesis and pharmacological evaluation of bis-3-(3,4-dichlorophenyl)acrylamide derivatives as glycogen phosphorylase inhibitors

2008 ◽  
Vol 16 (18) ◽  
pp. 8627-8634 ◽  
Author(s):  
Kenichi Onda ◽  
Ryota Shiraki ◽  
Yasuhiro Yonetoku ◽  
Kazuhiro Momose ◽  
Naoko Katayama ◽  
...  
Keyword(s):  
Glycogen Phosphorylase ◽  
Pharmacological Evaluation ◽  
Glycogen Phosphorylase Inhibitors

5-Chloroindoloyl glycine amide inhibitors of glycogen phosphorylase: synthesis, in vitro, in vivo, and X-ray crystallographic characterization

2005 ◽  
Vol 15 (2) ◽  
pp. 459-465 ◽  
Author(s):  
Stephen W. Wright ◽  
Virginia L. Rath ◽  
Paul E. Genereux ◽  
David L. Hageman ◽  
Carolyn B. Levy ◽  
...  
Keyword(s):  
Glycogen Phosphorylase ◽  
X Ray

scholarly journals Synthesis and in Vitro and in Vivo Pharmacological Evaluation of New 4-Aminoquinoline-Based Compounds

2013 ◽  
Vol 4 (12) ◽  
pp. 1198-1202 ◽  
Author(s):  
Matshawandile Tukulula ◽  
Mathew Njoroge ◽  
Efrem T. Abay ◽  
Grace C. Mugumbate ◽  
Lubbe Wiesner ◽  
...  
Keyword(s):  
Pharmacological Evaluation

Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl]phenyl}thiazoles as atypical antipsychotic agents

2012 ◽  
Vol 22 (4) ◽  
pp. 1660-1673 ◽  
Author(s):  
Kondapalli Venkata Gowri Chandra Sekhar ◽  
Vajja Sambasiva Rao ◽  
Winnie Deuther-Conrad ◽  
Divya Sridhar ◽  
Hunsur Nagendra Nagesh ◽  
...  
Keyword(s):  
Atypical Antipsychotic ◽  
Antipsychotic Agents ◽  
Design Synthesis ◽  
Pharmacological Evaluation ◽  
Atypical Antipsychotic Agents
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