J. Lipid Res. Acyl Labeled PIP's available August 1, 2008
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

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

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
M400436-JLR200v1
46/3/547    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Harwood, H. J.
Right arrow Articles by Treadway, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Harwood, H. J., Jr.
Right arrow Articles by Treadway, J. L.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
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


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
S. Ekins, D. C. Mankowski, D. J. Hoover, M. P. Lawton, J. L. Treadway, and H. J. Harwood Jr.
Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors
Drug Metab. Dispos., March 1, 2007; 35(3): 493 - 500.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
S. D. Hester, D. C. Wolf, S. Nesnow, and S.-F. Thai
Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil
Toxicol Pathol, December 1, 2006; 34(7): 879 - 894.
[Abstract] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Journal of Biological Chemistry 
 Molecular and Cellular Proteomics   ASBMB Today 
Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.