Novel ester and acid derivatives of the 1,5-diarylpyrrole scaffold as anti-inflammatory and analgesic agents. Synthesis and in vitro and in vivo biological evaluation.
A new generation of selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More recent clinical findings highlighted how the cardiovascular toxicity of coxibs could be mitigated by an appropriate COX-1 versus COX-2 selectivity. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, selective for COX-2. Here, we describe the synthesis of new 1,5-diarylpyrroles along with their inhibitory effects in vitro, ex vivo, and in vivo toward COX isoenzymes and their analgesic activity. Isopropyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole-3-acetate (10a), a representative member of the series, was selected for pharmacokinetic and metabolic studies.
Biava
Mariangela
M
Dipartimento di Studi di Chimica e Tecnologie del Farmaco, Università La Sapienza, piazzale Aldo Moro 5, I-00185 Roma, Italy. mariangela.biava@uniroma1.it
Porretta
Giulio C
GC
Poce
Giovanna
G
Battilocchio
Claudio
C
Manetti
Fabrizio
F
Botta
Maurizio
M
Forli
Stefano
S
Sautebin
Lidia
L
Rossi
Antonietta
A
Pergola
Carlo
C
Ghelardini
Carla
C
Galeotti
Nicoletta
N
Makovec
Francesco
F
Giordani
Antonio
A
Anzellotti
Paola
P
Patrignani
Paola
P
Anzini
Maurizio
M
D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D002264:Carboxylic Acids; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D004952:Esters; D020128:Inhibitory Concentration 50; D008264:Macrophages; D051379:Mice; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002264:Carboxylic Acids; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004952:Esters; D011758:Pyrroles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2