An orally active antidiabetic agent, THR-0940 is a non-thiazolidinedione, combined PPARalpha/gamma agonist. In preliminary experiments, THR-0940 demonstrated both glucose and triglyceride lowering activity in rodent models of diabetes and insulin resistance. The Phase I research plan is designed to further characterize the antidiabetic, triglyceride lowering, and antihypertensive activities of THR-0940. Three animal models that are relevant to the metabolic disturbances in type 2 diabetes (hyperglycemia, hypertriglyceridemia, and hypertension) will be used to evaluate the pharmacodynamic profile of THR-0940. Obese, insulin-resistant db/db mice will be used to evaluate the antidiabetic effect of THR-0940. Important dose response data will be generated in these studies. Insulin-resistant, hyperlipidemic, non-diabetic fat-fed rats will be used to investigate the triglyceride lowering effect of THR-0940. Insulin-resistant SHR rats will be used to evaluate the antihypertensive activity of THR-0940. Comparisons with other active antidiabetic and triglyceride lowering drugs will be made as a measure to gauge a potential advantage of THR-0940 over currently available drugs. Data from these studies will further characterize the potential of THR-0940 for treatment of type 2 diabetes and will provide valuable information to qualify this molecule for entry into clinical development.
