Novel Analgesic/Anti-Inflammatory Agents: Diarylpyrrole Acetic Esters Endowed with Nitric Oxide Releasing Properties

被引：43

作者：

Biava, Mariangela ^{[1
]}

Porretta, Giulio Cesare ^{[1
]}

Poce, Giovanna ^{[1
]}

Battilocchio, Claudio ^{[1
]}

Alfonso, Salvatore ^{[1
]}

Rovini, Michele ^{[2
]}

Valenti, Salvatore ^{[2
]}

Giorgi, Gianluca ^{[3
]}

Calderone, Vincenzo ^{[4
]}

Martelli, Alma ^{[4
]}

Testai, Lara ^{[4
]}

Sautebin, Lidia ^{[5
]}

Rossi, Antonietta ^{[5
]}

Papa, Giuseppina ^{[5
]}

Ghelardini, Carla ^{[6
]}

Mannelli, Lorenzo Di Cesare ^{[6
]}

Giordani, Antonio ^{[7
]}

Anzellotti, Paola ^{[8
,9
]}

Bruno, Annalisa ^{[8
,9
]}

Patrignani, Paola ^{[8
,9
]}

Anzini, Maurizio ^{[2
]}

机构：

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

[2] Univ Siena, Dipartimento Farmaco Chimico Tecnol, I-53100 Siena, Italy

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

[4] Univ Pisa, Dipartimento Psichiatria Neurobiol Farmacol, I-56126 Pisa, Italy

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

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

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

[8] Univ GDAnnunzio Chieti, Dipartimento Med & Sci Invecchiamento, I-66100 Chieti, Italy

[9] Ctr Sci Invecchiamento CeSI, I-66100 Chieti, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 22期

关键词：

BIOLOGICAL EVALUATION; 1,5-DIARYLPYRROLE SCAFFOLD; GASTROINTESTINAL TOXICITY; IN-VITRO; CYCLOOXYGENASE-2; INHIBITORS; DOCKING SIMULATIONS; ACID-DERIVATIVES; COX-2; ROFECOXIB; CELECOXIB;

D O I：

10.1021/jm200715n

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：

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.

引用

页码：7759 / 7771

页数：13

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