Synthesis, Biological Evaluation, and Enzyme Docking Simulations of 1,5-Diarylpyrrole-3-Alkoxyethyl Ethers as Selective Cyclooxygenase-2 Inhibitors Endowed with Anti-inflammatory and Antinociceptive Activity

A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers (6, 7, and 8) has been synthesized with the aim to assess if in the previously reported 1,5-diarylpyrrole derivatives (5) the replacement of the acetic ester moiety with an alkoxyethyl group still led to new, highly selective and potent...

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Published in:Journal of medicinal chemistry 2008-08, Vol.51 (15), p.4476-4481
Main Authors: Anzini, Maurizio, Rovini, Michele, Cappelli, Andrea, Vomero, Salvatore, Manetti, Fabrizio, Botta, Maurizio, Sautebin, Lidia, Rossi, Antonietta, Pergola, Carlo, Ghelardini, Carla, Norcini, Monica, Giordani, Antonio, Makovec, Francesco, Anzellotti, Paola, Patrignani, Paola, Biava, Mariangela
Format: Article
Language:English
Subjects:
Analgesics
Analgesics - chemical synthesis
Analgesics - chemistry
Analgesics - pharmacology
Animals
Anti-Inflammatory Agents - chemical synthesis
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacology
Anti-Inflammatory Agents - therapeutic use
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Computer Simulation
Cyclooxygenase 2 Inhibitors - chemical synthesis
Cyclooxygenase 2 Inhibitors - chemistry
Cyclooxygenase 2 Inhibitors - pharmacology
Cyclooxygenase 2 Inhibitors - therapeutic use
Edema - drug therapy
Ether - chemical synthesis
Ether - chemistry
Ether - pharmacology
Ether - therapeutic use
Humans
Hydrophobic and Hydrophilic Interactions
Male
Medical sciences
Mice
Models, Molecular
Molecular Structure
Neuropharmacology
Pharmacology. Drug treatments
Pyrroles - chemistry
Rats
Structure-Activity Relationship
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Summary:A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers (6, 7, and 8) has been synthesized with the aim to assess if in the previously reported 1,5-diarylpyrrole derivatives (5) the replacement of the acetic ester moiety with an alkoxyethyl group still led to new, highly selective and potent COX-2 inhibitors. In the in vitro cell culture assay, all the compounds proved to be potent and selective COX-2 inhibitors. In the human whole blood (HWB) assay, compound 8a had a comparable COX-2 selectivity to valdecoxib, while it was more selective than celecoxib but less selective than rofecoxib. The potential anti-inflammatory and antinociceptive activities of compounds 7a, 8a, and 8d were evaluated in vivo, where they showed a very good activity against both carrageenan-induced hyperalgesia and edema in the rat paw test. In the abdominal constriction test compound 7a, 8a, and 8d were able to reduce the number of writhes in a statistically significant manner. Furthermore, the affinity data of these compounds have been rationalized through enzyme docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site by means of the software package Autodock 3.0.5, GRID 21, and MacroModel 8.5 using the complex between COX-2 and SC-558 (1b), refined at a 3 Å resolution (Brookhaven Protein Data Bank entry: )
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800084s