Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/cyclooxygenase-1 selectivity.
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.
Biava
Mariangela
M
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
Porretta
Giulio Cesare
GC
Poce
Giovanna
G
Supino
Sibilla
S
Forli
Stefano
S
Rovini
Michele
M
Cappelli
Andrea
A
Manetti
Fabrizio
F
Botta
Maurizio
M
Sautebin
Lidia
L
Rossi
Antonietta
A
Pergola
Carlo
C
Ghelardini
Carla
C
Vivoli
Elisa
E
Makovec
Francesco
F
Anzellotti
Paola
P
Patrignani
Paola
P
Anzini
Maurizio
M
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
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