title: Enlarging the NSAIDs family: ether, ester and acid derivatives of the 1,5-diarylpyrrole scaffold as novel anti-inflammatory and analgesic agents.
abstract: The development of the coxib family has represented a stimulating approach in the treatment of inflammatory disorders, such as arthritis, and for the management of acute pains, in relation to the well-known traditional Non-Steroidal Anti-inflammatory Drugs (t-NSAIDs). Prompted by the pursuit for new cyclooxygenase-2 (COX-2) inhibitors, endowed with fine tuned selectivity and high potency, in the past years we have identified novel classes of ether, ester and acid molecules characterized by the 1,5-diarylpyrrole scaffold as potentially powerful anti-inflammatory molecules (12-66). All compounds proved to exert an in vitro inhibition profile as good as that shown by reference compounds. Compounds bearing a p-methylsulfonylphenyl substituent at C5 displayed the best issues. In particular, ester derivatives proved to perform the best in vitro profile in terms of selectivity and activity toward COX-2. The cell-based assay data showed that an increase of hindrance at the C3 side chain of compounds could translate to activity enhancement. The human whole blood (HWB) test let to highlight that submitted compounds displayed 5-10 fold higher selectivity for COX-2 vs COX-1 which should translate clinically to an acceptable gastrointestinal safety and mitigate the cardiovascular effects highlighted by highly selective COX-2 inhibitors. Finally, to assess in vivo anti-inflammatory and analgesic activity three different tests (rat paw pressure, rat paw oedema and abdominal constriction) were performed. Results showed good in vivo anti-inflammatory and analgesic activities. The issues gained with these classes of compounds represent, nowadays, a potent stimulus for a further enlargement of the NSAIDs family. In this review we describe the results obtained by our research group on this topic.
authors.affiliation: 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.forename: M
authors.initials: M
authors.lastname: Biava
authors.forename: G C
authors.initials: GC
authors.lastname: Porretta
authors.forename: G
authors.initials: G
authors.lastname: Poce
authors.forename: C
authors.initials: C
authors.lastname: Battilocchio
authors.forename: M
authors.initials: M
authors.lastname: Botta
authors.forename: F
authors.initials: F
authors.lastname: Manetti
authors.forename: M
authors.initials: M
authors.lastname: Rovini
authors.forename: A
authors.initials: A
authors.lastname: Cappelli
authors.forename: L
authors.initials: L
authors.lastname: Sautebin
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: C
authors.initials: C
authors.lastname: Pergola
authors.forename: C
authors.initials: C
authors.lastname: Ghelardini
authors.forename: N
authors.initials: N
authors.lastname: Galeotti
authors.forename: F
authors.initials: F
authors.lastname: Makovec
authors.forename: A
authors.initials: A
authors.lastname: Giordani
authors.forename: P
authors.initials: P
authors.lastname: Anzellotti
authors.forename: S
authors.initials: S
authors.lastname: Tacconelli
authors.forename: P
authors.initials: P
authors.lastname: Patrignani
authors.forename: M
authors.initials: M
authors.lastname: Anzini
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011758:Pyrroles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2