Novel analgesic/anti-inflammatory agents: diarylpyrrole acetic esters endowed with nitric oxide releasing properties |
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Authors: | Biava Mariangela Porretta Giulio Cesare Poce Giovanna Battilocchio Claudio Alfonso Salvatore Rovini Michele Valenti Salvatore Giorgi Gianluca Calderone Vincenzo Martelli Alma Testai Lara Sautebin Lidia Rossi Antonietta Papa Giuseppina Ghelardini Carla Di Cesare Mannelli Lorenzo Giordani Antonio Anzellotti Paola Bruno Annalisa Patrignani Paola Anzini Maurizio |
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Institution: | Dipartimento di Studi di Chimica e Tecnologie del Farmaco, Università "Sapienza", Piazzale Aldo Moro 5, I-00185 Roma, Italy. mariangela.biava@uniroma1.it |
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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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