1. Novel Analgesic/Anti-Inflammatory Agents: 1,5-Diarylpyrrole Nitrooxyalkyl Ethers and Related Compounds as Cyclooxygenase-2 Inhibiting Nitric Oxide Donors
- Author
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Anzini, Maurizio, Di Capua, Angela, Valenti, Salvatore, Brogi, Simone, Rovini, Michele, Giuliani, Germano, Cappelli, Andrea, Vomero, Salvatore, Chiasserini, Luisa, Sega, Alessandro, Poce, Giovanna, Giorgi, Gianluca, Calderone, Vincenzo, Martelli, Alma, Testai, Lara, Sautebin, Lidia, Rossi, Antonietta, Pace, Simona, Ghelardini, Carla, Di Cesare Mannelli, Lorenzo, Benetti, Veronica, Giordani, Antonio, Anzellotti, Paola, Dovizio, Melania, Patrignani, Paola, and Biava, Mariangela
- Abstract
A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7–10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17and 18were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,cand 17ahighlighted good anti-inflammatory and antinociceptive activities. Compound 9cwas able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling and 1H- and 13C-NMR studies performed on compounds 6c,d, 9c, and 10ballowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed.
- Published
- 2024
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