title: Slowing down fat digestion and absorption by an oxadiazolone inhibitor targeting selectively gastric lipolysis.
abstract: 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".
authors.affiliation: Aix-Marseille Univ, CNRS, EIPL, Marseille, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Point
authors.affiliation: Aix-Marseille Univ, CNRS, EIPL, Marseille, France.
authors.forename: Anais
authors.initials: A
authors.lastname: Bénarouche
authors.affiliation: Aix-Marseille Univ, CNRS, EIPL, Marseille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Zarrillo
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 - CNRS - UM - ENSCM, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Guy
authors.affiliation: ITERG-ENMS, Université de Bordeaux, rue Léo Saignat, 33076 Bordeaux Cedex, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Magnez
authors.affiliation: ITERG-ENMS, Université de Bordeaux, rue Léo Saignat, 33076 Bordeaux Cedex, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Fonseca
authors.affiliation: Aix-Marseille Univ, CNRS, EIPL, Marseille, France.
authors.forename: Brigitt
authors.initials: B
authors.lastname: Raux
authors.affiliation: Aix-Marseille Univ, CNRS, Centrale Marseille, ISM2, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Leclaire
authors.affiliation: Aix-Marseille Univ, CNRS, Centrale Marseille, ISM2, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Buono
authors.affiliation: Aix-Marseille Univ, CNRS, Centrale Marseille, ISM2, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fotiadu
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 - CNRS - UM - ENSCM, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Durand
authors.affiliation: Aix-Marseille Univ, CNRS, EIPL, Marseille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Carrière
authors.affiliation: ITERG-ENMS, Université de Bordeaux, rue Léo Saignat, 33076 Bordeaux Cedex, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Vaysse
authors.affiliation: ITERG-ENMS, Université de Bordeaux, rue Léo Saignat, 33076 Bordeaux Cedex, France. Electronic address: l.couedelo@iterg.com.
authors.forename: Leslie
authors.initials: L
authors.lastname: Couëdelo
authors.affiliation: Aix-Marseille Univ, CNRS, EIPL, Marseille, France. Electronic address: jfcavalier@imm.cnrs.fr.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cavalier
mesh_terms: D000818:Animals; D004063:Digestion / Q000187:drug effects*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007700:Kinetics; D008049:Lipase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D013270:Stomach / Q000187:drug effects*
chemical_list: C586624:1,3,4-oxadiazol-2(3H)-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D008049:Lipase
keywords: Digestive enzyme; Enzyme inhibition; Gastrointestinal digestion; Intestinal absorption; Lipases; Lymphatic lipids; Oxadiazolone