Development of non-peptidic inverse agonists of the ghrelin receptor (GHSR) based on the 1,2,4-triazole scaffold

Khoubaib Ben Haj Salah (1) , Mathieu Maingot (1) , Anne-Laure Blayo (1) , Céline M'Kadmi (1) , Marjorie Damian (1) , Sophie Mary (1) , Sonia Cantel (1) , Jérémie Neasta (1) , Catherine Oiry (1) , Sylvie Péraldi-Roux (1) , Gimena Fernandez (2) , Guadalupe García Romero (2) , Mario Perello (2) , Jacky Marie (1) , Jean-Louis Banères (1) , Jean-Alain Fehrentz (1) , Séverine Denoyelle (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 IMBICE - Instituto Multidisciplinario de Biología Celular [La Plata]

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, 2 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.

Mots clés: Agonists; Ligand; Peptides and proteins; Receptors; Rodent models

Domaines: Chimie

Khoubaib Ben Haj Salah, Mathieu Maingot, Anne-Laure Blayo, Céline M'Kadmi, Marjorie Damian, et al.. Development of non-peptidic inverse agonists of the ghrelin receptor (GHSR) based on the 1,2,4-triazole scaffold. Journal of Medicinal Chemistry, 2020, 63 (19), pp.10796-10815. ⟨10.1021/acs.jmedchem.9b02122⟩. ⟨hal-03027489⟩