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Bruno A.,University of Chieti Pescara | Di Francesco L.,University of Chieti Pescara | Coletta I.,Randgelini Research Center | Mangano G.,Randgelini Research Center | And 10 more authors.
Biochemical Pharmacology

Inhibitors ofmicrosomal prostaglandin (PG) E synthase-1 (mPGES-1) are being developed for the relief of pain. Redirection of the PGH2 substrate to other PG synthases, found both in vitro and in vivo, in mPGES-1 knockoutmice, may influence their efficacy and safety.We characterized the contribution ofmPGES-1 to PGH2metabolism in lipopolysaccharide (LPS)-stimulated isolated human monocytes and whole blood by studying the synthesis of prostanoids [PGE2, thromboxane (TX)B2, PGF2a and 6-keto-PGF1a] and expression of cyclooxygenase (COX)-isozymes and down-stream synthases in the presence of pharmacological inhibition by the novel mPGES-1 inhibitor AF3442 [N-(9-ethyl-9H-carbazol-3-yl)- 2- (trifluoromethyl)benzamide]. AF3442 caused a concentration-dependent inhibition of PGE2 in human recombinant mPGES-1 with an IC50 of 0.06 mM. In LPS-stimulated monocytes, AF3442 caused a concentration-dependent reduction of PGE2 biosynthesis with an IC50 of 0.41 mM. At 1 mM, AF3442 caused maximal selective inhibitory effect of PGE2 biosynthesis by 61 ± 3.3% (mean ± SEM, P < 0.01 versus DMSO vehicle) without significantly affecting other prostanoids (i.e. TXB2, PGF2α and 6-keto-PGF17alpha;). In LPS-stimulated whole blood, AF3442 inhibited in a concentration-dependent fashion inducible PGE2 biosynthesis with an IC 50 of 29 μM. A statistically significant inhibition of mPGES-1 activity was detected at 10 and 100 μM(38 ± 14%, P < 0.05, and 69 ± 5%, P < 0.01, respectively). Up to 100 mM, the other prostanoids were not significantly affected. In conclusion, AF3442 is a selective mPGES-1 inhibitor which reduced monocyte PGE2 generation also in the presence of plasma proteins. Pharmacological inhibition of mPGES-1 did not translate into redirection of PGH2 metabolismtowards other terminal PG synthases in monocytes. The functional relevance of this observation deserves to be investigated in vivo. © 2009 Elsevier Inc. All rights reserved. Source

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