ABSTRACT
Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Indazoles/pharmacology , Receptors, Estrogen/antagonists & inhibitors , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Indazoles/administration & dosage , Indazoles/chemistry , Ligands , Male , Mice , Mice, Obese , Molecular Structure , Rats , Rats, Sprague-Dawley , Rats, Zucker , Structure-Activity Relationship , ERRalpha Estrogen-Related ReceptorABSTRACT
Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.
Subject(s)
Drug Design , Imidazoles/chemistry , Phosphodiesterase Inhibitors/chemistry , Phosphoric Diester Hydrolases/chemistry , Pyridines/chemistry , Animals , Binding Sites , Glucose Tolerance Test , Half-Life , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Insulin/metabolism , Molecular Docking Simulation , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphoric Diester Hydrolases/metabolism , Protein Binding , Protein Structure, Tertiary , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 µM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.
