ly-465608 and Diabetes-Mellitus--Type-2

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Models, Molecular; Molecular Structure; Receptors, Cytoplasmic and Nuclear; Transcription Factors

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.

Topics: Animals; Binding, Competitive; Cell Line; Diabetes Mellitus, Type 2; Female; Humans; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Phenylpropionates; Radioligand Assay; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Stereoisomerism; Structure-Activity Relationship; Thiophenes; Transcription Factors

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 ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot 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 cardiovascular 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.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Dose-Response Relationship, Drug; Energy Intake; Energy Metabolism; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Male; Metabolic Syndrome; Mice; Mice, Mutant Strains; Organic Chemicals; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors

Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.

Topics: Animals; Blood Glucose; Cholesterol, HDL; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Design; Hypoglycemic Agents; Mice; Mice, Inbred Strains; Propionates; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Triglycerides