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.