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

被引：51

作者：

Anzini, Maurizio ^{[1
]}

Di Capua, Angela ^{[1
]}

Valenti, Salvatore ^{[1
]}

Brogi, Simone ^{[1
]}

Rovini, Michele ^{[1
]}

Giuliani, Germano ^{[1
]}

Cappelli, Andrea ^{[1
]}

Vomero, Salvatore ^{[1
]}

Chiasserini, Luisa ^{[1
]}

Sega, Alessandro ^{[1
]}

Poce, Giovanna ^{[2
]}

Giorgi, Gianluca ^{[3
,4
]}

Calderone, Vincenzo ^{[3
,4
]}

Martelli, Alma ^{[3
,4
]}

Testai, Lara ^{[3
,4
]}

Sautebin, Lidia ^{[5
]}

Rossi, Antonietta ^{[5
]}

Pace, Simona ^{[5
]}

Ghelardini, Carla ^{[6
]}

Mannelli, Lorenzo Di Cesare ^{[6
]}

Benetti, Veronica ^{[7
]}

Giordani, Antonio ^{[8
]}

Anzellotti, Paola ^{[9
,10
]}

Dovizio, Melania ^{[9
,10
]}

Patrignani, Paola ^{[9
,10
]}

Biava, Mariangela ^{[2
]}

机构：

[1] Univ Siena, Dipartimento Farmaco Chim Tecnol, I-53100 Siena, Italy

[2] Univ Roma La Sapienza, Dipartimento Studi Chim & Tecnol Farmaco, I-00185 Rome, Italy

[3] Univ Siena, Dipartimento Chim, I-53100 Siena, Italy

[4] Univ Pisa, Dipartimento Psichiat Neurobiol Farmacol & Biotec, I-56126 Pisa, Italy

[5] Univ Naples Federico II, Dipartimento Farm, I-80131 Naples, Italy

[6] Univ Florence, Dipartimento Farmacol, I-50139 Florence, Italy

[7] Innovat Biotech, I-56121 Pisa, Italy

[8] Rottapharm Madaus, I-20052 Monza, Italy

[9] Univ G dAnnunzio, Dipartimento Neurosci & Imaging, I-66100 Chieti, Italy

[10] CeSI, I-66100 Chieti, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 08期

关键词：

INDUCED EXPERIMENTAL OSTEOARTHRITIS; NUCLEAR-MAGNETIC-RESONANCE; PHARMACOLOGICAL CHARACTERIZATION; PHARMACODYNAMIC HYBRIDS; BIOLOGICAL EVALUATION; BLOOD-PRESSURE; FORCE-FIELD; IN-VITRO; DYNAMICS; ACID;

D O I：

10.1021/jm301370e

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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 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 beta (IL-1 beta), showing cartilage protective properties. Finally, molecular modeling and H-1- and C-13-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.

引用

页码：3191 / 3206

页数：16

共 70 条

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