Synthesis and pharmacological evaluation of indolinone derivatives as novel ghrelin receptor antagonists

The ghrelin receptor is a G-protein-coupled receptor (GPCR) widely expressed in the brain, stomach and the intestine. It was firstly identified during studies aimed to find synthetic modulators of growth hormone (GH) secretion. GHSR and its endogenous ligand ghrelin were found to be involved in hunger response. Through food intake regulation, they could affect body weight and adiposity. Thus GHSR antagonists rapidly became an attractive target to treat obesity and feeding disorders. In this study we describe the biological properties of new indolinone derivatives identified as a new, chiral class of ghrelin antagonists. Their synthesis as well as the structure-activity relationship will be discussed herein. The in vitro identified compound 14f was a potent GHSR1a antagonist (IC(50)=7nM). When tested in vivo, on gastric emptying model, 14f showed an inhibitory intrinsic effect when given alone and it dose dependently inhibited ghrelin stimulation. Compound 14f also reduced food intake stimulated both by fasting condition (high level of endogenous ghrelin) and by icv ghrelin. Moreover this compound improved glucose tolerance in ipGTT test.