ABSTRACT
Novel tetrahydroisoquinolines have been developed as potent PPAR ligands. Evaluation of these compounds in PPARgamma responsive models of type 2 diabetes is described.
Subject(s)
Hypoglycemic Agents/pharmacology , PPAR gamma/agonists , Tetrahydroisoquinolines/pharmacology , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Mice , Models, Molecular , PPAR gamma/drug effects , Peroxisome Proliferator-Activated Receptors/antagonists & inhibitors , Rosiglitazone , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/pharmacokinetics , Thiazolidinediones/pharmacologyABSTRACT
PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.
Subject(s)
Cinnamates/chemical synthesis , Cinnamates/pharmacokinetics , Peroxisome Proliferator-Activated Receptors/physiology , Humans , Hypoglycemic Agents/therapeutic use , Ligands , PPAR alpha/physiology , PPAR gamma/physiology , Structure-Activity Relationship , Thiazolidinediones/chemical synthesis , Thiazolidinediones/therapeutic useABSTRACT
Herein we describe a series of potent and selective PPARgamma agonists with moderate PPARalpha affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.
Subject(s)
Cinnamates/pharmacology , Diabetes Mellitus, Type 2/metabolism , Peroxisome Proliferator-Activated Receptors/agonists , Animals , Blood Glucose/metabolism , Cinnamates/administration & dosage , Cinnamates/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Rats , Rats, Zucker , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
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.
