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Journal of Lipid Research, Vol. 46, 547-563, March 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Dual-action hypoglycemic and hypocholesterolemic agents that inhibit glycogen phosphorylase and lanosterol demethylase

H. James Harwood, Jr.^1,*, Stephen F. Petras^*, Dennis J. Hoover^*, Dayna C. Mankowski^*, Victor F. Soliman^*, Eliot D. Sugarman^*, Bernard Hulin^*, Younggil Kwon^*, E. Michael Gibbs^*, James T. Mayne and Judith L. Treadway^*

^* Departments of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Eastern Point Road, Groton, CT 06340
Exploratory Toxicology, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Eastern Point Road, Groton, CT 06340

¹ To whom correspondence should be addressed. e-mail: h_james_harwood{at}groton.pfizer.com

Diabetic dyslipidemia requires simultaneous treatment with hypoglycemic agents and lipid-modulating drugs. We recently described glycogen phosphorylase inhibitors that reduce glycogenolysis in cells and lower plasma glucose in ob/ob mice (J. Med. Chem., 41: 2934, 1998). In evaluating the series prototype, CP-320626, in dogs, up to 90% reduction in plasma cholesterol was noted after 2 week treatment. Cholesterol reductions were also noted in ob/ob mice and in rats. In HepG2 cells, CP-320626 acutely and dose-dependently inhibited cholesterolgenesis without affecting fatty acid synthesis. Inhibition occurred together with a dose-dependent increase in the cholesterol precursor, lanosterol, suggesting that cholesterolgenesis inhibition was due to lanosterol 14-demethylase (CYP51) inhibition. In ob/ob mice, acute treatment with CP-320626 resulted in a decrease in hepatic cholesterolgenesis with concomitant lanosterol accumulation, further implicating CYP51 inhibition as the mechanism of cholesterol lowering in these animals. CP-320626 and analogs directly inhibited rhCYP51, and this inhibition was highly correlated with HepG2 cell cholesterolgenesis inhibition (R² = 0.77).

These observations indicate that CP-320626 inhibits cholesterolgenesis via direct inhibition of CYP51, and that this is the mechanism whereby CP-320626 lowers plasma cholesterol in experimental animals. Dual-action glycogenolysis and cholesterolgenesis inhibitors therefore have the potential to favorably affect both the hyperglycemia and the dyslipidemia of type 2 diabetes.

Supplementary key words cholesterol synthesis • glycogenolysis • glycogen phosphorylase • lanosterol 14-demethylase • CYP51 • enzyme inhibition • type 2 diabetes • HepG2 cells • ob/ob mice

Abbreviations: AUC, area under the curve; CYP, cytochrome-P450; DMEM, Dulbecco's modified Eagle's medium

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