Development of Nonpeptidic Inverse Agonists of the Ghrelin Receptor (GHSR) Based on the 1,2,4-Triazole Scaffold

BLAYO, ANNE-LAURE; MARY, SOPHIE; OIRY, CATHERINE; ROMERO, GUADALUPE GARCÍA; BANÈRES, JEAN-LOUIS; HAJ SALAH, KHOUBAIB BEN; M'KADMI, CÉLINE; CANTEL, SONIA; PÉRALDI-ROUX, SYLVIE; PERELLO, MARIO; FEHRENTZ, JEAN-ALAIN; MAINGOT, MATHIEU; DAMIAN, MARJORIE; NEASTA, JÉRÉMIE; FERNANDEZ, GIMENA; MARIE, JACKY; DENOYELLE, SÉVERINE

JOURNAL OF MEDICINAL CHEMISTRY

AMER CHEMICAL SOC

Año: 2020 vol. 63 p. 10796 - 10815

0022-2623

GHSR controls, among others, growth hormone and insulin secretion, adiposity, feeding, and glucose metabolism. Therefore, an inverse agonist ligand capable of selectively targeting GHSR and reducing its high constitutive activity appears to be a good candidate for the treatment of obesity-related metabolic diseases. In this context, we present a study that led to the development of several highly potent and selective inverse agonists of GHSR based on the 1,2,4-triazole scaffold. We demonstrate that, depending on the nature of the substituents on positions 3, 4, and 5, this scaffold leads to ligands that exert an intrinsic inverse agonist activity on GHSR-catalyzed G protein activation through the stabilization of a specific inactive receptor conformation. Thanks to an in vivo evaluation, we also show that one of the most promising ligands not only exerts an effect on insulin secretion in rat pancreatic islets but also affects the orexigenic effects of ghrelin in mice.