Identification of novel microsomal prostaglandin E2 synthase-1 (mPGES-1) lead inhibitors from Fragment Virtual Screening.

European journal of medicinal chemistry 2017 Jan 05

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Identification of new microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors is currently sought for the treatment of cancer and inflammation. Here we show the results of a Fragment Virtual Screening campaign using the X-ray crystal structure of human mPGES-1 (PDB code: 4AL0). Among the fragments selected and biologically tested, 6 (9H-indeno [1,2-b] [1,2,5]oxadiazolo [3,4-e]pyrazin-9-one) showed the most promising mPGES-1 inhibitory activity (∼30% inhibition at 10 μM). A minimal structure-based optimization of 6 led to compounds 15, 20 and 21, with a promising enhancement of the inhibitory activity (IC50 = 4.6 ± 0.2 μM for 15; IC50 = 2.4 ± 1.0 μM for 20; IC50 = 2.4 ± 0.8 μM for 21). The unprecedented chemical core and the possibility of synthesizing novel derivatives reveal a new and attractive field of action for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties. Copyright Â© 2016 Elsevier Masson SAS. All rights reserved.

Citation

Gianluigi Lauro, Michele Manfra, Silvana Pedatella, Katrin Fischer, Vincenza Cantone, Stefania Terracciano, Alessia Bertamino, Carmine Ostacolo, Isabel Gomez-Monterrey, Mauro De Nisco, Raffaele Riccio, Ettore Novellino, Oliver Werz, Pietro Campiglia, Giuseppe Bifulco. Identification of novel microsomal prostaglandin E2 synthase-1 (mPGES-1) lead inhibitors from Fragment Virtual Screening. European journal of medicinal chemistry. 2017 Jan 05;125:278-287