Cyclooxygenase-2 Inhibitors. 1,5-Diarylpyrrol-3-acetic Esters with Enhanced Inhibitory Activity toward Cyclooxygenase-2 and Improved Cyclooxygenase-2/Cyclooxygenase-1 Selectivity

• Published in: Journal of medicinal chemistry Vol. 50; no. 22; pp. 5403 - 5411
• Main Authors: Biava, Mariangela, Porretta, Giulio Cesare, Poce, Giovanna, Supino, Sibilla, Forli, Stefano, Rovini, Michele, Cappelli, Andrea, Manetti, Fabrizio, Botta, Maurizio, Sautebin, Lidia, Rossi, Antonietta, Pergola, Carlo, Ghelardini, Carla, Vivoli, Elisa, Makovec, Francesco, Anzellotti, Paola, Patrignani, Paola, Anzini, Maurizio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.11.2007; Amer Chemical Soc
• Subjects: Acetates - chemical synthesis; Acetates - chemistry; Acetates - pharmacology; Adult; Analgesics; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carrageenan; Cell Line; Chemistry, Medicinal; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Dinoprostone - blood; Edema - chemically induced; Edema - prevention & control; Female; Humans; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Models, Molecular; Neuropharmacology; Pain Measurement; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Rats, Wistar; Science & Technology; Structure-Activity Relationship; T-Box Domain Proteins - blood; TRIALS; POTENT; COX-2 INHIBITION; METAANALYSIS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; HEALTHY-SUBJECTS; BIOLOGICAL EVALUATION; RISK; AGENTS; ASPIRIN; Enzyme; Cyclooxygenase 2; Rodentia; Enzyme inhibitor; Cyclooxygenase 2 inhibitor; Selectivity; Celecoxib; Acetic acid derivative; In vitro; Biological activity; Pyrrole derivatives; Non steroidal antiinflammatory agent; In vivo; Vertebrata; Mammalia; Analgesic; Structure activity relation; Mouse; Animal; Oxidoreductases; Fluorine Organic compounds; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0707525

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.