Design of group IIA secreted/synovial phospholipase A(2) inhibitors: an oxadiazolone derivative suppresses chondrocyte prostaglandin E(2) secretion.
Group IIA secreted/synovial phospholipase A(2) (GIIAPLA(2)) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E(2) (PGE(2)), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA(2) enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA(2), along with their chemical synthesis and results from PLA(2) inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA(2) affinities than did C1, and such predictions were confirmed by in vitro PLA(2) enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA(2) inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1beta-stimulated PGE(2) secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints.
Ombetta
Jean-Edouard
JE
Laboratoire de Chimie Organique, Faculté de Pharmacie, Université François Rabelais, Tours, France.
Thelier
Natacha
N
Dong
Chang Zhi
CZ
Plocki
Stéphanie
S
Tsagris
Lydia
L
Rannou
François
F
Massicot
France
F
Djimdé
Atimé
A
El-Hayek
Elissar
E
Shi
Yiming
Y
Heymans
Françoise
F
Gresh
Nohad
N
Chauvet
Caroline
C
D000818:Animals; D002460:Cell Line; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D064801:Phospholipase A2 Inhibitors; D011817:Rabbits
D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D064801:Phospholipase A2 Inhibitors; D015232:Dinoprostone