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Papers In Press, published online ahead of print December 16, 2004
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Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340
Corresponding Author: h_james_harwood{at}groton.pfizer.com
Diabetic dyslipidemia requires simultaneous treatment with hypoglycemic agents and lipid-modulating drugs. We recently described a series of glycogen phosphorylase inhibitors that reduce glycogenolysis in SK-HEP-1 cells and lower plasma glucose levels in ob/ob mice (J. Med. Chem. 41: 2934, 1998). In evaluating the series prototype, CP-320626, in dogs, marked (up to 90%) reduction in plasma cholesterol was noted after 2-week treatment. Significant cholesterol reductions were also noted in ob/ob mice and in rats. To determine the mechanism for this cholesterol lowering, we evaluated the ability of CP-320626 to inhibit cholesterolgenesis in HepG2 cells and in ob/ob mice. 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 a consequence of lanosterol 14a-demethylase (CYP51) inhibition. In ob/ob mice, acute administration of CP-320626 also resulted in a dose-dependent decrease in hepatic cholesterolgenesis with concomitant lanosterol accumulation, further implicating CYP51 inhibition as the mechanism of cholesterol lowering in these animals. When CP-320626 analogs were evaluated for their ability to directly inhibit recombinant human CYP51, HepG2 cell cholesterolgenesis inhibition was highly correlated with CYP51 inhibition (R2 = 0.77). CP-320626 and analogs also exhibited a high specificity for CYP51 inhibition versus CYP3A4, CYP2C9 and CYP2D6 inhibition, indicating that CYP51 inhibition was due to specific association with CYP51 and not due to interference with the cytochrome P450 reaction mechanism or with NADPH-cytochrome P450 reductase. Together these observations indicate that CP-320626 and analogs inhibit cholesterolgenesis via direct inhibition of CYP51, and that this is the mechanism whereby CP-320626 lowers plasma cholesterol in experimental animals. These dual action glycogenolysis and cholesterolgenesis inhibitors, therefore have the potential to favorably affect both the hyperglycemia and dyslipidemia of type-2 diabetes.
Revised on December 3, 2004
Accepted on December 3, 2004
Dual-action hypoglycemic and hypocholesterolemic agents that inhibit glyogen phosphorylase and lanosterol 14
-demethylase (CYP51)
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