CP 91,149

CP 91,149 is an inhibitor of human liver glycogen phosphorylase a (LGPa), muscle glycogen phosphorylase a (MGPa), and MGPb (IC₅₀s = 0.13, 0.2, and 0.3 μM, respectively, in the presence of glucose).^1,2,3 CP 91,149 is 5- to 10-fold less potent in the absence of glucose.¹ In vitro, it inhibits glucagon-stimulated glycogenolysis in primary human hepatocytes (IC₅₀ = 2.1 μM) and increases glycogen synthesis in rat hepatocytes at a concentration of 2.5 μM in the presence of 5 mM glucose.^1,3 CP 91,149 inhibits brain GP (IC₅₀ = 0.5 μM) and, at a concentration of 30 μM, inhibits glycogen accumulation and proliferation of A549 non-small cell lung carcinoma (NSCLC) cells that express endogenous brain GP.⁴ In vivo, CP 91,149 (25 mg/kg, p.o.) lowers the plasma glucose level in diabetic ob/ob mice within 3 hours of administration without producing hypoglycemia, but has no effect on normoglycemic, non-diabetic mice.¹

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1. Martin, W.H., Hoover, D.J., Armento, S.J., et al. Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo. Proc. Natl. Acad. Sci. USA 95(4), 1776-1781 (1998).

2. Hoover, D.J., Lefkowitz-Snow, S., Burgess-Henry, J.L., et al. Indole-2-carboxamide inhibitors of human liver glycogen phosphorylase. J. Med. Chem. 41(16), 2934-2938 (1998).

3. Aiston, S., Hampson, L., Gómez-Foix, A.M., et al. Hepatic glycogen synthesis is highly sensitive to phosphorylase activity: Evidence from metabolic control analysis. The Journal of Biological Chemisty 276(26), 23858-23866 (2001).

4. Schnier, J.B., Nishi, K., Monks, A., et al. Inhibition of glycogen phosphorylase (GP) by CP-91,149 induces growth inhibition correlating with brain GP expression. Biochem. Biophys. Res. Commun. 309(1), 126-134 (2003).