title: 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.
abstract: 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.
authors: Dipartimento di Studi di Chimica e Tecnologie del Farmaco, Università La Sapienza, piazzale Aldo Moro 5, I-00185 Roma, Italy. mariangela.biava@uniroma1.it
authors: Mariangela
authors: M
authors: Biava
authors: Giulio C
authors: GC
authors: Porretta
authors: Giovanna
authors: G
authors: Poce
authors: Claudio
authors: C
authors: Battilocchio
authors: Fabrizio
authors: F
authors: Manetti
authors: Maurizio
authors: M
authors: Botta
authors: Stefano
authors: S
authors: Forli
authors: Lidia
authors: L
authors: Sautebin
authors: Antonietta
authors: A
authors: Rossi
authors: Carlo
authors: C
authors: Pergola
authors: Carla
authors: C
authors: Ghelardini
authors: Nicoletta
authors: N
authors: Galeotti
authors: Francesco
authors: F
authors: Makovec
authors: Antonio
authors: A
authors: Giordani
authors: Paola
authors: P
authors: Anzellotti
authors: Paola
authors: P
authors: Patrignani
authors: Maurizio
authors: M
authors: Anzini
mesh_terms: 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
chemical_list: 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