Details

Autor(en) / Beteiligte

• Lauro, Gianluigi
• Manfra, Michele
• Pedatella, Silvana
• Fischer, Katrin
• Cantone, Vincenza
• Terracciano, Stefania
• Bertamino, Alessia
• Ostacolo, Carmine
• Gomez-Monterrey, Isabel
• De Nisco, Mauro
• Riccio, Raffaele
• Novellino, Ettore
• Werz, Oliver
• Campiglia, Pietro
• Bifulco, Giuseppe

Titel

Identification of novel microsomal prostaglandin E 2 synthase-1 (mPGES-1) lead inhibitors from Fragment Virtual Screening

Ist Teil von

• European journal of medicinal chemistry, 2017-01, Vol.125, p.278

Ort / Verlag

France

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• Identification of new microsomal prostaglandin E 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 (IC  = 4.6 ± 0.2 μM for 15; IC  = 2.4 ± 1.0 μM for 20; IC  = 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.