ABSTRACT
The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.
Subject(s)
Diabetes Mellitus/drug therapy , Obesity/drug therapy , Quinazolinones/chemical synthesis , Receptors, Ghrelin/antagonists & inhibitors , Administration, Oral , Animals , Binding, Competitive , Blood Glucose/analysis , Cell Line , Eating/drug effects , Glucose Tolerance Test , Humans , Male , Mice , Mice, Inbred C57BL , Quinazolinones/chemistry , Quinazolinones/pharmacology , Radioligand Assay , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity Relationship , Weight Loss/drug effectsABSTRACT
A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.
Subject(s)
Insulin Resistance , PPAR delta/agonists , Fluorescence Resonance Energy Transfer , Structure-Activity RelationshipABSTRACT
Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.
Subject(s)
Insulin/metabolism , Islets of Langerhans/drug effects , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Quinolines/pharmacology , Drug Design , Humans , Insulin Secretion , Islets of Langerhans/metabolism , Molecular Structure , Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases/drug effects , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models.
Subject(s)
Acetates/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Indans/chemical synthesis , PPAR alpha/agonists , PPAR delta/agonists , PPAR gamma/agonists , Triazoles/chemical synthesis , Acetates/chemistry , Acetates/pharmacology , Animals , Apolipoprotein A-I/genetics , Cell Line , Cricetinae , Female , Humans , Hyperlipidemias/drug therapy , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Indans/chemistry , Indans/pharmacology , Lipids/blood , Male , Mice , Mice, Transgenic , PPAR alpha/genetics , PPAR gamma/genetics , Radioligand Assay , Rats , Rats, Zucker , Solubility , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
Modulation of PPAR activities represents an attractive approach for the treatment of diabetes with associated cardiovascular complications. The indanylacetic acid structural motif has proven useful in the generation of potent and tunable PPAR ligands. Modification of the substituents on the linker and the heterocycle tail group allowed for the modulation of the selectivity at the different receptor subtypes. Compound 33 was evaluated in vivo, where it displayed the desired reduction of glucose levels and increase in HDL levels in various animal models.
