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. Journal of medicinal chemistry [J Med Chem] Journal article | | Title | 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. | | Author(s) | Anzini M, Rovini M, Cappelli A, Vomero S, Manetti F, Botta M, Sautebin L, Rossi A, Pergola C, Ghelardini C, Norcini M, Giordani A, Makovec F, Anzellotti P, Patrignani P, Biava M | | Institution | Dipartimento Farmaco Chimico Tecnologico, Universita di Siena, Via A. Moro, 53100 Siena, Italy, Dipartimento di Farmacologia Sperimentale, Universita di Napoli "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy, IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo-C. da Casazza, I-98124 Messina, Italy, Dipartimento di Farmacologia Preclinica e Clinica "M. Aiazzi Mancini", Universita degli Studi di Firenze, Viale G. Pieraccini 6, 50139 Firenze, Italy, Rottapharm S.p.A., Via Valosa di Sopra 7, 20052 Monza, Italy, Dipartimento di Medicina e Scienze dell'Invecchiamento, Sezione di Farmacologia, Universita di Chieti "G. D'Annunzio" e CeSI, Via dei Vestini 31, 66013 Chieti, Italy, Dipartimento di Chimica e Tecnologie del Farmaco, Universita "La Sapienza", Ple A. Moro 5, I-00185 Roma, Italy anzini@unisi.it. | | Source | J Med Chem 2008 Jul 4. | | Abstract | 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 A resolution (Brookhaven Protein Data Bank entry: 6cox ). | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18598017 |
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