- Design and synthesis of a second series of triazole-based compounds as potent dual mPGES-1 and 5-lipoxygenase inhibitors
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Microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO) are pivotal enzymes in the biosynthesis of the pro-inflammatory PGE2 and leukotrienes, respectively. The design and synthesis of a second series of mPGES-1 inhibitors based on a triazole scaffold are described. Our studies allowed us to draw a tentative SAR profile and to optimize this series with the identification of compounds 10, 11 and 14-15 which displayed potent mPGES-1 inhibition in a cell-free assay. In addition, compounds 5, 10, 12 and 14-16 also blocked 5-LO activity in cell-free and cell-based test systems, emerging as very promising candidates for the development of safer and more effective anti-inflammatory drugs.
- Chini, Maria Giovanna,De Simone, Rosa,Bruno, Ines,Riccio, Raffaele,Dehm, Friederike,Weinigel, Christina,Barz, Dagmar,Werz, Oliver,Bifulco, Giuseppe
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- Structure-based discovery of inhibitors of microsomal prostaglandin E 2 synthase-1, 5-lipoxygenase and 5-lipoxygenase-activating protein: Promising hits for the development of new anti-inflammatory agents
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Microsomal prostaglandin E2 synthase (mPGES)-1 catalyzes the transformation of PGH2 to PGE2 that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC50 value of 3.2 μ-M, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC50 = 0.4 μ-M).
- De Simone, Rosa,Chini, Maria Giovanna,Bruno, Ines,Riccio, Raffaele,Mueller, Daniela,Werz, Oliver,Bifulco, Giuseppe
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supporting information; experimental part
p. 1565 - 1575
(2011/06/26)
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