A Tailored Therapy for the Metabolic Syndrome

A Tailored Therapy for the Metabolic Syndrome The Dual Peroxisome Proliferator-Activated Receptor-α/γ Agonist LY465608 Ameliorates Insulin Resistance and Diabetic Hyperglycemia While Improving Cardiovascular Risk Factors in Preclinical Models Garret J. Etgen 1 , Brian A. Oldham 1 , William T. Johnson 1 , Carol L. Broderick 1 , Chahrzad R. Montrose 1 , Joseph T. Brozinick 1 , Elizabeth A. Misener 1 , James S. Bean 2 , William R. Bensch 2 , Dawn A. Brooks 3 , Anthony J. Shuker 3 , Christopher J. Rito 3 , James R. McCarthy 3 , Robert J. Ardecky 4 , John S. Tyhonas 4 , Sharon L. Dana 5 , James M. Bilakovics 5 , James R. Paterniti, Jr 5 , Kathleen M. Ogilvie 5 , Sha Liu 5 and Raymond F. Kauffman 2 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 Abstract A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-α/γ 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 ED 50 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-γ agonist, which were presumably due to the concomitant PPAR-α 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 cardiovac