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.
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 ).
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Universita di Siena, Siena, Italy. anzini@unisi.it
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Michele
authors.initials: M
authors.lastname: Rovini
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Monica
authors.initials: M
authors.lastname: Norcini
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.forename: Paola
authors.initials: P
authors.lastname: Anzellotti
authors.forename: Paola
authors.initials: P
authors.lastname: Patrignani
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D003198:Computer Simulation; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy; D004986:Ether / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D011758:Pyrroles; D004986:Ether