title: Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/cyclooxygenase-1 selectivity.
abstract: The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3-acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain.
authors.affiliation: Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università La Sapienza, piazzale Aldo Moro 5, I-00185 Roma, Italy. mariangela.biava@uniroma1.it
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
authors.forename: Giulio Cesare
authors.initials: GC
authors.lastname: Porretta
authors.forename: Giovanna
authors.initials: G
authors.lastname: Poce
authors.forename: Sibilla
authors.initials: S
authors.lastname: Supino
authors.forename: Stefano
authors.initials: S
authors.lastname: Forli
authors.forename: Michele
authors.initials: M
authors.lastname: Rovini
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
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: Elisa
authors.initials: E
authors.lastname: Vivoli
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: Maurizio
authors.initials: M
authors.lastname: Anzini
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000328:Adult; D000818:Animals; D002351:Carrageenan; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000097:blood; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010147:Pain Measurement; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D020825:T-Box Domain Proteins / Q000097:blood
chemical_list: D000085:Acetates; D052246:Cyclooxygenase 2 Inhibitors; D011758:Pyrroles; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; C524708:ethyl 2-methyl-5-(4-(methylsulfonyl)phenyl)-1-(3-fluorophenyl)-1H-pyrrol-3-acetate; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone