yil-781 and Obesity

Substituted azaquinazolinones were identified as antagonists of the GHSr-1A receptor for the treatment of type II diabetes and obesity. Optimisation for potency and LogD lead to the identification of orally bioavailable, potent antagonists with improved selectivity over hERG.

Topics: Administration, Oral; Animals; Aza Compounds; Biological Availability; Diabetes Mellitus, Type 2; Drug Design; Ether-A-Go-Go Potassium Channels; Humans; Hydrophobic and Hydrophilic Interactions; Hypoglycemic Agents; Kinetics; Male; Obesity; Quinazolinones; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Structure-Activity Relationship

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.

Topics: Administration, Oral; Animals; Binding, Competitive; Blood Glucose; Cell Line; Diabetes Mellitus; Eating; Glucose Tolerance Test; Humans; Male; Mice; Mice, Inbred C57BL; Obesity; Quinazolinones; Radioligand Assay; Rats; Rats, Wistar; Receptors, Ghrelin; Stereoisomerism; Structure-Activity Relationship; Weight Loss