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

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 (<b>7</b>–<b>10</b>) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (<b>9</b>, <b>10</b>) into corresponding alcohols, derivatives <b>17</b> and <b>18</b> 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 <b>9a</b>,<b>c</b> and <b>17a</b> highlighted good anti-inflammatory and antinociceptive activities. Compound <b>9c</b> was 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 <b>6c</b>,<b>d</b>, <b>9c</b>, and <b>10b</b> allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed