title: Design of new potent and selective secretory phospholipase A(2) inhibitors. 6-Synthesis, structure-activity relationships and molecular modelling of 1-substituted-4-[4,5-dihydro-1,2,4-(4H)-oxadiazol-5-one-3-yl(methyl)]-functionalized aryl piperazin/one/dione derivatives.
abstract: The group IIA human non-pancreatic secretory phospholipase A(2) (hnp-sPLA(2)) is one of the enzymes implied in the inflammatory process. In the course of our work on inhibitors of this enzyme we investigated the influence of rigidity of the piperazine region on the biological activity. Several modifications were explored. Various linkers, such as amide, urea, carbamate, or alkoxyphenyl were inserted between the piperazine and the lipophilic chain. Also, modification of the piperazine core to incorporate carbonyl groups was studied. In an in vitro fluorimetric assay using the human GIIA (HPLA(2)) and porcine pancreatic GIB enzymes, compound 60a (Y=phenoxy, R=C(18)H(37), Z=CH(2)) had the optimal activity with an IC(50)=30nM on HPLA(2). By means of molecular modelling we attempted to get informations towards comprehension of differences in activity.
authors.affiliation: Laboratoire ITODYS, équipe Pharmacochimie Moléculaire, Université Paris Diderot, 15 rue de Baïf, 75205 Paris Cedex 13, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Meddad-Belhabich
authors.forename: Darina
authors.initials: D
authors.lastname: Aoun
authors.forename: Atimé
authors.initials: A
authors.lastname: Djimdé
authors.forename: Catherine
authors.initials: C
authors.lastname: Redeuilh
authors.forename: Georges
authors.initials: G
authors.lastname: Dive
authors.forename: France
authors.initials: F
authors.lastname: Massicot
authors.forename: François
authors.initials: F
authors.lastname: Chau
authors.forename: Françoise
authors.initials: F
authors.lastname: Heymans
authors.forename: Aazdine
authors.initials: A
authors.lastname: Lamouri
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D000077489:Piperazine; D010741:Phospholipases A