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Diabetes 51:1083-1087, 2002
© 2002 by the American Diabetes Association, Inc.

A Tailored Therapy for the Metabolic Syndrome

The Dual Peroxisome Proliferator-Activated Receptor-{alpha}/{gamma} Agonist LY465608 Ameliorates Insulin Resistance and Diabetic Hyperglycemia While Improving Cardiovascular Risk Factors in Preclinical Models

Garret J. Etgen1, Brian A. Oldham1, William T. Johnson1, Carol L. Broderick1, Chahrzad R. Montrose1, Joseph T. Brozinick1, Elizabeth A. Misener1, James S. Bean2, William R. Bensch2, Dawn A. Brooks3, Anthony J. Shuker3, Christopher J. Rito3, James R. McCarthy3, Robert J. Ardecky4, John S. Tyhonas4, Sharon L. Dana5, James M. Bilakovics5, James R. Paterniti, Jr5, Kathleen M. Ogilvie5, Sha Liu5, and Raymond F. Kauffman2

1 Division of Endocrine Research, Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana
2 Division of Cardiovascular Research, Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana
3 Division of Discovery Chemistry, Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana
4 Department of Medicinal Chemistry, Ligand Pharmaceuticals, San Diego, California
5 Department of Pharmacology, Ligand Pharmaceuticals, San Diego, California

A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-{alpha}/{gamma} agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED50 for glucose normalization of 3.8 mg · kg-1 · day-1. Metabolic improvements were associated with enhanced insulin sensitivity, as demonstrated in female obese Zucker (fa/fa) rats using both oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. Further characterization of LY465608 revealed metabolic changes distinct from a selective PPAR-{gamma} agonist, which were presumably due to the concomitant PPAR-{alpha} agonism, lower respiratory quotient, and less fat accumulation, despite a similar impact on glycemia in male ZDF rats. In addition to these alterations in diabetic and insulin-resistant animals, LY465608 dose-dependently elevated HDL cholesterol and lowered plasma triglycerides in human apolipoprotein A-I transgenic mice, demonstrating that this compound significantly improves primary cardiovascular risk factors. Overall, these studies demonstrate that LY465608 beneficially impacts multiple facets of type 2 diabetes and associated cardiovacular risk, including those facets involved in the development of micro- and macrovascular complications, which are the major sources for morbidity and mortality in these patients.


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