title: Novel analgesic/anti-inflammatory agents: diarylpyrrole acetic esters endowed with nitric oxide releasing properties.
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.
authors: Dipartimento di Studi di Chimica e Tecnologie del Farmaco, Università "Sapienza", Piazzale Aldo Moro 5, I-00185 Roma, Italy. mariangela.biava@uniroma1.it
authors: Mariangela
authors: M
authors: Biava
authors: Giulio Cesare
authors: GC
authors: Porretta
authors: Giovanna
authors: G
authors: Poce
authors: Claudio
authors: C
authors: Battilocchio
authors: Salvatore
authors: S
authors: Alfonso
authors: Michele
authors: M
authors: Rovini
authors: Salvatore
authors: S
authors: Valenti
authors: Gianluca
authors: G
authors: Giorgi
authors: Vincenzo
authors: V
authors: Calderone
authors: Alma
authors: A
authors: Martelli
authors: Lara
authors: L
authors: Testai
authors: Lidia
authors: L
authors: Sautebin
authors: Antonietta
authors: A
authors: Rossi
authors: Giuseppina
authors: G
authors: Papa
authors: Carla
authors: C
authors: Ghelardini
authors: Lorenzo
authors: L
authors: Di Cesare Mannelli
authors: Antonio
authors: A
authors: Giordani
authors: Paola
authors: P
authors: Anzellotti
authors: Annalisa
authors: A
authors: Bruno
authors: Paola
authors: P
authors: Patrignani
authors: Maurizio
authors: M
authors: Anzini
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D003251:Constriction, Pathologic / Q000139:chemically induced / Q000517:prevention & control; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004952:Esters; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000085:Acetates; D052246:Cyclooxygenase 2 Inhibitors; D004952:Esters; D007527:Isoenzymes; D020030:Nitric Oxide Donors; D011758:Pyrroles; D014665:Vasodilator Agents