Design of new potent and selective secretory phospholipase A2 inhibitors. Part 5: synthesis and biological activity of 1-alkyl-4-[4,5-dihydro-1,2,4-[4H]-oxadiazol-5-one-3-ylmethylbenz-4'-yl(oyl)] piperazines.
Among the different PLA(2)s identified to date, the group IIA secretory PLA(2) (sPLA(2) GIIA) is implied in diverse pathological conditions. In this work we describe the synthesis, inhibitory activities, and structure-activity relationships (SAR) of a new class of substituted piperazine derivatives. The in vitro fluorimetric assay using two groups of enzymes, GIB and GIIA, revealed several compounds as highly potent inhibitors (IC(50)=0.1 microM). The in vivo activity assessed by ip or per os administration in a carrageenan-induced edema test in rats showed that two compounds proved to be as potent as indomethacin (10 mg/kg).
Boukli
Latifa
L
Laboratoire de Pharmacochimie Moléculaire, Unité de Pharmacochimie Moléculaire et Systèmes Membranaires E.A. 2381, Université Paris 7-Denis Diderot, Case 7066, 2 Place Jussieu, 75251 Paris Cedex 05, France.
Touaibia
Mohamed
M
Meddad-Belhabich
Nadia
N
Djimdé
Atimé
A
Park
Chang-Ha
CH
Kim
Jung-Joo
JJ
Yoon
Joo-Hyoung
JH
Lamouri
Aazdine
A
Heymans
Françoise
F
D000478:Alkylation; D000818:Animals; D001554:Benzene / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006859:Hydrogen / Q000737:chemistry*; D008745:Methylation; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine
D004791:Enzyme Inhibitors; D010080:Oxazoles; D010879:Piperazines; D006859:Hydrogen; D054497:Phospholipases A2, Secretory; D001554:Benzene