Novel Analgesic/Anti-Inflammatory Agents: 1,5-Diarylpyrrole Nitrooxyalkyl Ethers and Related Compounds as Cyclooxygenase-2 Inhibiting Nitric Oxide Donors

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• 作者：Maurizio Anzini ; Angela Di Capua ; Salvatore Valenti ; Simone Brogi ; Michele Rovini ; Germano Giuliani ; Andrea Cappelli ; Salvatore Vomero ; Luisa Chiasserini ; Alessandro Sega ; Giovanna Poce ; Gianluca Giorgi ; Vincenzo Calderone ; Alma Martelli ; Lara Testai ; Lidia Sautebin ; Antonietta Rossi ; Simona Pace ; Carla Ghelardini ; Lorenzo Di Cesare Mannelli ; Veronica Benetti ; Antonio Giordani ; Paola Anzellotti ; Melania Dovizio ; Paola Patrignani ; Mariangela Biava
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 25, 2013
• 年：2013
• 卷：56
• 期：8
• 页码：3191-3206
• 全文大小：594K
• 年卷期：v.56,no.8(April 25, 2013)
• ISSN：1520-4804

文摘

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鈥?b>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 17 and 18 were 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,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1尾 (IL-1尾), showing cartilage protective properties. Finally, molecular modeling and ¹H- and ¹³C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed.