Design of Group IIA Secreted/Synovial Phospholipase A2 Inhibitors: An Oxadiazolone Derivative Suppresses Chondrocyte Prostaglandin E2 Secretion

Group IIA secreted/synovial phospholipase A2 (GIIAPLA2) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E2 (PGE2), 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 GIIAPLA2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA2, along with their chemical synthesis and results from PLA2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA2 affinities than did C1, and such predictions were confirmed by in vitro PLA2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1β-stimulated PGE2 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

Synthèse et étude des relations structure-activité d'inhibiteurs spécifiques de la phospholipase A2 de groupe II (modélisation moléculaire)

L'inflammation joue un rôle prépondérant dans bon nombre de pathologies. Elle débute par la libération d'Acide Arachidonique grâce à une enzyme appelée la Phospholipase A2.Cet acide est alors transformé sous l'action de multiples enzymes en médiateurs inflammatoires très puissants. A ce jour, les seuls médicaments capables d'inhiber la PLA2 sont les glucocorticoïdes comme la cortisone, mais leurs effets indésirables reconnus ont incité la recherche à créer d'autres médicaments : les Anti-infammatoires non stéroïdiens (AINS), inhibant des enzymes en aval de la PLA2 dans la réaction d'inflammation. Non dépourvus d'effets secondaires, les AINS n'ont pas cependant la propriété de bloquer les autres voies importantes de l'inflammation, enparticulier la formation du facteur d'activation des plaquettes (PAF). Basée sur des analogies avec le substrat, notre laboratoire a découvert depuis 1999 une série de molécules capables de bloquer spécifiquement la PLA2. [...]The inflammatory reaction is a benefic process because of its self-defense property. However it can induce serious complications qualified as inflammatory pathologies.sPLA2-IIA plays a pivotal role in the propagation and amplification of inflammation. In many pathological situations, circulating sPLA2-IIA level correlates with the severity and illness outcome.Human non pancreatic secretory PLA2 (hnps-PLA2) of group II is associated with pathologies as acute pancreatitis, rhumatisms, septic shock... But until now, its role is not completely clarified [...]PARIS-BIUP (751062107) / SudocSudocFranceF