Point_2012_Eur.J.Med.Chem_58_452

Reference

Title : Analysis of the discriminative inhibition of mammalian digestive lipases by 3-phenyl substituted 1,3,4-oxadiazol-2(3H)-ones. - Point_2012_Eur.J.Med.Chem_58_452
Author(s) : Point V , Pavan Kumar KV , Marc S , Delorme V , Parsiegla G , Amara S , Carriere F , Buono G , Fotiadu F , Canaan S , Leclaire J , Cavalier JF
Ref : Eur Journal of Medicinal Chemistry , 58 :452 , 2012
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.

PubMedSearch : Point_2012_Eur.J.Med.Chem_58_452
PubMedID: 23153815
Gene_locus related to this paper: canfa-1lipg , cavpo-2plrp , human-CEL , human-PNLIP , human-PNLIPRP2 , pig-1plip

Related information

Mutation WT_cavpo-2plrp    WT_pig-1plip    WT_canfa-1lipg    WT_human-PNLIPRP2    WT_human-PNLIP    WT_human-CEL
Inhibitor WT_cavpo-2plrp    WT_pig-1plip    WT_canfa-1lipg    WT_human-PNLIPRP2    WT_human-PNLIP    WT_human-CEL    MPOX    MpPPOX    MmPPOX
Gene_locus WT_cavpo-2plrp    WT_pig-1plip    WT_canfa-1lipg    WT_human-PNLIPRP2    WT_human-PNLIP    WT_human-CEL    MPOX    MpPPOX    MmPPOX    canfa-1lipg    cavpo-2plrp    human-CEL    human-PNLIP    human-PNLIPRP2    pig-1plip

Citations formats

Point V, Pavan Kumar KV, Marc S, Delorme V, Parsiegla G, Amara S, Carriere F, Buono G, Fotiadu F, Canaan S, Leclaire J, Cavalier JF (2012)
Analysis of the discriminative inhibition of mammalian digestive lipases by 3-phenyl substituted 1,3,4-oxadiazol-2(3H)-ones.
Eur Journal of Medicinal Chemistry 58 :452

Point V, Pavan Kumar KV, Marc S, Delorme V, Parsiegla G, Amara S, Carriere F, Buono G, Fotiadu F, Canaan S, Leclaire J, Cavalier JF (2012)
Eur Journal of Medicinal Chemistry 58 :452