Article de Vanessa Pointª, Anais Bénaroucheª, Julie Zarrilloª , Alexandre Guy c, Romain Magnezᵈ, Laurence Fonsecaᵈ, Brigitt Rauxª, Julien Leclaireᵇ, Gérard Buonoᵇ, Frédéric Fotiaduᵇ, Thierry Durand c, Frédéric Carrièreª, Carole Vaysseᵈ, Leslie Couëdeloᵈ, Jean-François Cavalierª, publié dans European Journal of Medicinal Chemistry, vol. 123, 2016, p. 834-848
ª Aix-Marseille Univ, CNRS, EIPL, Marseille, France
ᵇ Aix-Marseille Univ, CNRS, Centrale Marseille, ISM2, France
c Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 – CNRS – UM – ENSCM, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France
ᵈ ITERG-ENMS, Université de Bordeaux, rue Léo Saignat, 33076 Bordeaux Cedex, France
Based on a previous study and in silico molecular docking experiments, we have designed and synthesized a new series of ten 5-Alkoxy-N-3-(3-PhenoxyPhenyl)-1,3,4-Oxadiazol-2(3H)-one derivatives (RmPPOX). These molecules were further evaluated as selective and potent inhibitors of mammalian digestive lipases : purified dog gastric lipase (DGL) and guinea pig pancreatic lipase related protein 2 (GPLRP2), as well as porcine (PPL) and human (HPL) pancreatic lipases contained in porcine pancreatic extracts (PPE) and human pancreatic juices (HPJ), respectively. These compounds were found to strongly discriminate classical pancreatic lipases (poorly inhibited) from gastric lipase (fully inhibited). Among them, the 5-(2-(Benzyloxy)ethoxy)-3-(3-PhenoxyPhenyl)-1,3,4-Oxadiazol-2(3H)-one (BemPPOX) was identified as the most potent inhibitor of DGL, even more active than the FDA-approved drug Orlistat. BemPPOX and Orlistat were further compared in vitro in the course of test meal digestion, and in vivo with a mesenteric lymph duct cannulated rat model to evaluate their respective impacts on fat absorption. While Orlistat inhibited both gastric and duodenal lipolysis and drastically reduced fat absorption in rats, BemPPOX showed a specific action on gastric lipolysis that slowed down the overall lipolysis process and led to a subsequent reduction of around 55% of the intestinal absorption of fatty acids compared to controls. All these data promote BemPPOX as a potent candidate to efficiently regulate the gastrointestinal lipolysis, and to investigate its link with satiety mechanisms and therefore develop new strategies to “fight against obesity”.