Novel analgesic/anti-inflammatory agents: diarylpyrrole acetic esters endowed with nitric oxide releasing properties

J Med Chem. 2011 Nov 24;54(22):7759-71. doi: 10.1021/jm200715n.

Mariangela Biava ¹, Giulio Cesare Porretta, Giovanna Poce, Claudio Battilocchio, Salvatore Alfonso, Michele Rovini, Salvatore Valenti, Gianluca Giorgi, Vincenzo Calderone, Alma Martelli, Lara Testai, Lidia Sautebin, Antonietta Rossi, Giuseppina Papa, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Antonio Giordani, Paola Anzellotti, Annalisa Bruno, Paola Patrignani, Maurizio Anzini

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Affiliation

1 Dipartimento di Studi di Chimica e Tecnologie del Farmaco, Università "Sapienza", Piazzale Aldo Moro 5, I-00185 Roma, Italy. mariangela.biava@uniroma1.it

PMID: 21992176 DOI: 10.1021/jm200715n

Abstract

The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.

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