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Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo.

Abstract
An inhibitor of human liver glycogen phosphorylase a (HLGPa) has been identified and characterized in vitro and in vivo. This substance, [R-(R*, S*)]-5-chloro-N-[3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)pr opyl]-1H-indole-2-carboxamide (CP-91149), inhibited HLGPa with an IC50 of 0.13 microM in the presence of 7.5 mM glucose. CP-91149 resembles caffeine, a known allosteric phosphorylase inhibitor, in that it is 5- to 10-fold less potent in the absence of glucose. Further analysis, however, suggests that CP-91149 and caffeine are kinetically distinct. Functionally, CP-91149 inhibited glucagon-stimulated glycogenolysis in isolated rat hepatocytes (P < 0.05 at 10-100 microM) and in primary human hepatocytes (2.1 microM IC50). In vivo, oral administration of CP-91149 to diabetic ob/ob mice at 25-50 mg/kg resulted in rapid (3 h) glucose lowering by 100-120 mg/dl (P < 0.001) without producing hypoglycemia. Further, CP-91149 treatment did not lower glucose levels in normoglycemic, nondiabetic mice. In ob/ob mice pretreated with 14C-glucose to label liver glycogen, CP-91149 administration reduced 14C-glycogen breakdown, confirming that glucose lowering resulted from inhibition of glycogenolysis in vivo. These findings support the use of CP-91149 in investigating glycogenolytic versus gluconeogenic flux in hepatic glucose production, and they demonstrate that glycogenolysis inhibitors may be useful in the treatment of type 2 diabetes.
AuthorsW H Martin, D J Hoover, S J Armento, I A Stock, R K McPherson, D E Danley, R W Stevenson, E J Barrett, J L Treadway
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 95 Issue 4 Pg. 1776-81 (Feb 17 1998) ISSN: 0027-8424 [Print] United States
PMID9465093 (Publication Type: Journal Article)
Chemical References
  • Amides
  • Blood Glucose
  • CP 91149
  • Enzyme Inhibitors
  • Indoles
  • Liver Glycogen
  • Recombinant Proteins
  • Caffeine
  • Phosphorylases
Topics
  • Amides (chemical synthesis, pharmacology)
  • Animals
  • Blood Glucose (metabolism)
  • Caffeine (pharmacology)
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 (drug therapy)
  • Enzyme Inhibitors (chemical synthesis, pharmacology)
  • Humans
  • Indoles (chemical synthesis, pharmacology)
  • Liver (cytology, enzymology)
  • Liver Glycogen (metabolism)
  • Male
  • Mice
  • Mice, Obese
  • Phosphorylases (antagonists & inhibitors)
  • Rats
  • Recombinant Proteins

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