J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400436-JLR200 on December 16, 2004

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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{dagger} 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
{dagger} 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{alpha}-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{alpha}-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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