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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.

Objective: To determine the consequences of pharmacologic up-regulation of heme oxygenase 1 (HO-1), and inhibition of HO-1 by injection of an anti-HO-1 small interfering RNA (siRNA), in vivo in the acute phase of a mouse model of nonautoimmune arthritis., Methods: In the K/BxN mouse serum transfer model, which mimics human inflammatory arthritis without lymphocyte influence, HO-1 was up-regulated by intraperitoneal injection of cobalt protoporphyrin IX (CoPP), a potent pharmacologic inducer, and was inhibited using a specific siRNA. The clinical progress of arthritis was monitored by measurement of paw thickness. Interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNFalpha), serum antioxidant, and nitric oxide (NO) levels, prostaglandin E(2) (PGE(2)) production, and matrix metalloproteinase 9 (MMP-9) activity were measured in serum. At the end of the experiments, joints were examined for immunohistopathologic changes., Results: Intraperitoneal injection of CoPP alleviated disease symptoms, such as joint swelling, cartilage degradation, and proliferation of inflammatory tissue in joints, in the acute phase of inflammatory arthritis. The CoPP-induced expression of HO-1 in the joints and liver was associated with marked decreases in IL-1beta, IL-6, and TNFalpha levels, PGE(2) secretion, and MMP-9 activity in serum, and with a marked increase in systemic antioxidant activity. In contrast, NO production in serum and inducible NO synthase expression in chondrocytes were not affected by HO-1 induction. Specific inhibition of HO-1 by in vivo delivery of anti-HO-1 siRNA repressed the protective effects., Conclusion: Our data provide the first evidence that pharmacologically induced up-regulation of HO-1 triggers a robust protective antiinflammatory response in a model of nonautoimmune arthritis in mice. This suggests that exogenously induced HO-1 may have potential as therapy in the acute phase of inflammatory arthritis in humans.