title: Analysis of the discriminative inhibition of mammalian digestive lipases by 3-phenyl substituted 1,3,4-oxadiazol-2(3H)-ones.
abstract: We report here the reactivity and selectivity of three 5-Methoxy-N-3-Phenyl substituted-1,3,4-Oxadiazol-2(3H)-ones (MPOX, as well as meta and para-PhenoxyPhenyl derivatives, i.e.MmPPOX and MpPPOX) with respect to the inhibition of mammalian digestive lipases: dog gastric lipase (DGL), human (HPL) and porcine (PPL) pancreatic lipases, human (HPLRP2) and guinea pig (GPLRP2) pancreatic lipase-related proteins 2, human pancreatic carboxyl ester hydrolase (hCEH), and porcine pancreatic extracts (PPE). All three oxadiazolones displayed similar inhibitory activities on DGL, PLRP2s and hCEH than the FDA-approved anti-obesity drug Orlistat towards the same enzymes. These compounds appeared however to be discriminative of HPL (poorly inhibited) and PPL (fully inhibited). The inhibitory activities obtained experimentally in vitro were further rationalized using in silico molecular docking. In the case of DGL, we demonstrated that the phenoxy group plays a key role in specific molecular interactions within the lipase's active site. The absence of this group in the case of MPOX, as well as its connectivity to the neighbouring aromatic ring in the case of MmPPOX and MpPPOX, strongly impacts the inhibitory efficiency of these oxadiazolones and leads to a significant gain in selectivity towards the lipases tested. The powerful inhibition of PPL, DGL, PLRP2s, hCEH and to a lesser extend HPL, suggests that oxadiazolone derivatives could also provide useful leads for the development of novel and more discriminative inhibitors of digestive lipases. These inhibitors could be used for a better understanding of individual lipase function as well as for drug development aiming at the regulation of the whole gastrointestinal lipolysis process.
authors.affiliation: CNRS - Aix-Marseille Université - Enzymologie Interfaciale et Physiologie de Lipolyse - UMR 7282, 31 chemin Joseph Aiguier, 13402 Marseille Cedex 20, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Point
authors.forename: K V P
authors.initials: KV
authors.lastname: Pavan Kumar
authors.forename: Sylvain
authors.initials: S
authors.lastname: Marc
authors.forename: Vincent
authors.initials: V
authors.lastname: Delorme
authors.forename: Goetz
authors.initials: G
authors.lastname: Parsiegla
authors.forename: Sawsan
authors.initials: S
authors.lastname: Amara
authors.forename: Frédéric
authors.initials: F
authors.lastname: Carrière
authors.forename: Gérard
authors.initials: G
authors.lastname: Buono
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fotiadu
authors.forename: Stéphane
authors.initials: S
authors.lastname: Canaan
authors.forename: Julien
authors.initials: J
authors.lastname: Leclaire
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cavalier
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011994:Recombinant Proteins; D008049:Lipase